Deborah J Marsh*1 and Roberto T Zori2
1Cancer Genetics, Kolling Institute of Medical Research and Department of Molecular Medicine, The University of Sydney, Sydney, Australia;
2Department of Pediatrics, University of Florida, Gainesville, Florida, USA.
*Corresponding author: Phone +61 2 9926 7176; FAX +61 2 9926 8484; E-mail Debbie_Marsh@med.usyd.edu.au
Key words: Familial cancer syndromes; hereditary tumour; Knudson’s ‘2-hit’; genetic testing; tumour suppressor gene; oncogene
Abstract
While the vast majority of cancers are believed to occur sporadically, most forms of cancer, both adult and paediatric, have a hereditary equivalent. In the case of adult malignancies, these include hereditary breast and ovarian cancer and syndromes such as the Multiple Endocrine Neoplasias Types 1 and 2 characterised by specific tumours of the endocrine gland system. In the case of paediatric malignancies, these include syndromes such as Retinoblastoma and Wilms Tumour. In a little over a single decade, we have seen a tremendous increase in the knowledge of the primary genetic basis of many of the familial cancer syndromes. The majority of familial syndromes are inherited as autosomal dominant traits including hereditary colon cancer and familial malignant melanoma, however the genetics behind autosomal recessive disorders such as Bloom Syndrome and Fanconi Anaemia are also being elucidated. A third mode of inheritance less well understood in the setting of familial cancer is that of imprinting recently observed in a subset of families with inherited paraganglioma. In this review, we discuss 31 genes inherited in an autosomal dominant manner associated with 20 familial cancer syndromes. Genes inherited in an autosomal recessive manner linked to familial cancer syndromes are also discussed. The identification of genes associated with familial cancer syndromes has in some families enabled a ‘molecular diagnosis’ that complements clinical assessment and allows directed cancer surveillance for those individuals determined to be at-risk of disease.
iNTRODUCTION
A number of familial cancers have been recognised as syndromic for well over 100 years, however their elucidation at the molecular level has only occurred recently. Retinoblastoma, a paediatric malignancy of the retina, was first linked to the tumour suppressor gene (TSG) RB1 in 1988. Since then, a further 30 genes have been linked to some 19 familial syndromes shown to be inherited in an autosomal dominant manner (Fig. 1), some syndromes such as Li-Fraumeni Syndrome (LFS) showing genetic heterogeneity with 2 causal genes functioning in similar pathways– TP53 and hCHK2. Many of the familial cancer syndromes are characterised by the presence of multiple tumours, such as seen in Cowden Syndrome (CS), often complicating clinical diagnosis given that the susceptibility loci involved target multiple tissues rather than specific sites. In these cases, a molecular diagnosis can be of great assistance to the clinical management of the affected individual as appropriate directed cancer surveillance can be implemented.
The majority of the genes associated with familial cancer syndromes would appear to function as TSGs, with only three genes to date, RET, MET and CDK4, functioning as oncogenes in respectively Multiple Endocrine Neoplasia Type 2 (MEN 2), Hereditary Papillary Renal Cell Carcinoma (HPRCC) and Familial Malignant Melanoma (FMM). It is likely that the critical role of many of the oncogenes during normal embryogenesis precludes abrogation of their normal function being compatible with life. TSGs have been further classified based on their roles as ‘gatekeepers’ or ‘caretakers’ [1]. Gatekeeper genes directly regulate the growth of tumour cells by controlling cellular proliferation or promoting cell death, ie. they act as negative regulators of the malignant potential of a cell. Examples of gatekeeper genes are TP53 in LFS, APC in Familial Adenomatous Polyposis Coli (FAP) and VHL in von Hippel Lindau Disease (VHL). Caretaker genes are responsible for maintaining the genetic stability of a cell, ie they maintain the genome’s integrity and indirectly promote tumour growth by causing an increased mutation rate. Caretaker genes include those responsible for Hereditary Nonpolyposis Colorectal Cancer (HNPCC), an autosomal dominantly inherited condition, as well as those linked to conditions inherited in an autosomal recessive fashion such as Xeroderma Pigmentosum (XP).
While it is clear that familial cancers develop on the background of an initiating germline mutation, the development and progression of tumours requires additional genetic events that may be the abrogation of function of the wild-type allele of many TSGs already mutated in the germline (see Knudson’s Hypothesis below), as well as the accumulation of additional events in somatic cells in other TSGs or oncogenes. This, in some part, is likely to explain the increasing age-related penetrance of the tumourigenic phenotype seen in many of the inherited cancers. Further, modifier or low penetrance loci may also influence the development of tumours and account for some of the differences in expressivity seen both within and between families with the identical cancer syndrome.
HIGHLY PENETRANT GENE LOCI – CATALYSTS FOR HEREDITARY CANCER
Knudson’s ‘2-Hit’ Hypothesis - Then and Now
Knudson’s original ‘2-hit’ hypothesis was conceived to explain the development of retinoblastoma and was later expanded to include all hereditary cancers (reviewed in 2]. Most simply, Knudson’s ‘2-hit’ hypothesis states that the first ‘hit’ in the development of a familial tumour occurs in the germline in a cancer susceptibility gene and the second ‘hit’ occurs somatically in the other allele of the same gene. Knudson’s hypothesis also extends to encompass the development of sporadic tumours, with the 2 ‘hits’ occurring somatically, affecting both alleles of the susceptibility gene. The positional cloning strategies employed to map many of the genes associated with familial cancer discussed in this review have incorporated the theory behind Knudson’s model by identifying regions of loss of heterozygosity (LOH) in tumours, allowing the isolation of susceptibility genes with identification of a mutation in the retained allele.
It has been observed that deletions, especially whole gene deletions, are quite rare in the germline, yet far more common in somatic cells, suggesting that whole gene deletions may be especially deleterious to the developing embryo, while somatic deletions are likely more tolerated in individual cells and may occur more commonly as a spontaneous event than point or frameshift type mutations [2]. Allelic loss is seen in many familial tumours including PTEN-associated thyroid tumours in CS and SMAD4-associated juvenile polyps in Juvenile Polyposis Coli (JPS).
Recently, Knudson’s model has been expanded to include concepts such as the methylator phenotype [3], haploinsufficiency (eg. PTEN) [4], ‘third’ hits involving loss of either tumour suppressor allele after the first ‘2-hits’ have occurred (eg. APC) [5], and allelic loss dependent upon the location of a germline mutation (eg. APC) [reviewed in 2].
AUTOSOMAL DOMINANT FAMILIAL CANCER DISORDERS
Clinical Evidence for the Presence of Highly Penetrant Cancer Genes in Families
The first scholars to alert us in the published literature to cases of inherited cancer in families were Sir James Paget of England and Paul Broca of France in the 1800’s [reviewed in 6]. The clinical observations of Broca with regards to the family of ‘Madame Z.’ spanning 3 generations of female breast cancer are still made today when ascertaining whether a family has an increased susceptibility to malignancy likely due to the mutation of a high penetrance cancer susceptibility gene.
Phenotypic and epidemiological evidence can signal the likely presence of a highly penetrant cancer gene in families that may be a new mutation (de novo) or have been present for generations. The following 6 points may be used as a guideline for establishing the presence of familial cancer:
- Tumour development in an individual(s) at a much younger age than that normally observed in the population for specific tumour types believed to occur sporadically, often < 30 years.
- The presence of bilateral disease in an individual(s) unlikely to be the result of metastases, eg. phaeo in both adrenal glands or bilateral breast cancer, or multiple disease sites in the one organ, eg. colorectal carcinoma (CRC) developing from multiple polyps.
- The presentation of greater than one type of cancer (multiple primary malignancies), eg. breast and thyroid cancer as seen in CS, in a single individual(s).
- The presentation of cancer in the less usually affected sex, eg. breast cancer in a male in conjunction with female breast cancer in related individuals.
- Clustering of the same cancer type in related individuals.
- Cancer associated with other conditions such as mental retardation or lentiginoses, for eg. melanin pigmentation seen in Peutz-Jeghers Syndrome (PJS).
The Syndromes
The autosomal dominantly inherited familial syndromes have been grouped as follows for this review – endocrine neoplasia syndromes, intestinal cancer syndromes, breast and ovarian cancer syndromes, skin carcinoma syndromes, the neurofibromatoses, renal carcinoma syndromes and paediatric syndromes. Given that a number of the syndromes discussed have multiple sites of tumour development, they could equally have been grouped under different headings. Detailed mutation summaries for all of the genes discussed are available at the Human Gene Mutation Database (http://archive.uwcm.ac.uk/uwcm/mg/hgmd0.html). A summary of the predominant tumours associated with each syndrome and the function or classification of each gene is given (Table 1). The location of each gene is also reported (Table 1) (Fig. 2). Syndromes where loci have been identified but mapping of the susceptibility gene(s) has not been reported are not discussed in depth in this review.
The Endocrine Neoplasia Syndromes:
In a broad sense, the endocrine neoplasia syndromes are categorised by the presence of germline mutations predisposing hormone secreting cells to become neoplastic, either by loss of the function of a TSG such as is seen in CS, Multiple Endocrine Neoplasia Type 1 (MEN 1) and VHL, or gain of function of an oncogene as is the case of RET in MEN 2. MEN 2 was the first of the inherited endocrine neoplasia syndromes to be elucidated at the genetic level with the discovery in 1993 that germline mutations in the RET proto-oncogene were present in affected individuals [7]. As one of the earliest familial cancer syndromes to be clarified at the molecular level, MEN 2 has become a model for the incorporation of molecular medicine into patient care.
Multiple Endocrine Neoplasia Type 2 (MEN 2)
Clinical Features
The penetrance of MEN 2 (OMIM#171400) is zero at the time of birth and increases with age so that by 70 years, two thirds of gene carriers will have presented with features of this syndrome [8]. MEN 2 can be divided into 3 sub-types, each with medullary thyroid carcinoma (MTC) as their primary component tumour. MTC is a malignant tumour of the calcitonin-secreting parafollicular C-cells originating in the embryonic neural crest. The precursor lesion for MTC within MEN 2 is C-cell hyperplasia. Twenty-five percent of MTCs develop as part of the MEN 2 syndrome, the remainder being sporadic. The frequency of inherited MTC in the general population is believed to be 1 in 25 000 to 30 000 [9, 10].
In the first MEN 2 sub-type, MEN 2A, MTC occurs in conjunction with tumours of the adrenal medulla (phaeo) in 50% of cases, and with hyperparathyroidism in 15-30% of cases [reviewed in 11]. MEN 2B is the most aggressive of the 3 sub-types, often displaying an earlier age of onset and in addition to MTC, other stigmata including mucosal neuromas, a Marfanoid habitus, and ganglioneuromatosis of the gastrointestinal tract. Of interest, hyperparathyroidism is only rarely seen in MEN 2B. FMTC is perhaps the mildest presentation of the syndrome, often displaying a later age of onset and with MTC being the sole phenotype. Whilst the additional stigmata of MEN 2B distinguish it from the other sub-types, it is possible that some small FMTC families are in fact MEN 2A families that have not yet developed a phaeo or hyperparathyroidism. For this reason, individuals who are members of FMTC families should undergo identical cancer surveillance procedures to those from MEN 2A families [reviewed in 12]. Two other syndromes have been reported to occur in MEN 2A / FMTC families, namely Cutaneous Lichen Amyloidosis (OMIM#105250) and Hirschsprung Disease (OMIM #142623).
Molecular Determinants – the RET proto-oncogene
The RET (REarranged during Transformation) gene is made up of at least 21 exons spanning over 55 kb of genomic DNA [13], maps to 10q11.2 and encodes a transmembrane receptor tyrosine kinase. Alternative splicing at both the 5’ and 3’ ends of RET predicted to generate multiple protein isoforms has been reported [14]. At the 3’ end of RET, alternative splicing generates transcripts that encode 3 protein isoforms, RET9, RET43 and RET51 that would seem to have specialised signalling properties, especially during development of the embryonic kidney [15]. RET would appear to have a role in the proliferation, migration and differentiation of neural crest derived cell lineages [16].
The large extracellular domain of RET, including a cadherin-like domain and a cysteine-rich region, allows the recognition and binding of RET’s ligand – co-receptor complexes. The RET tyrosine kinase domain lies intracellularly and is necessary for autophosphorylation of activated RET, the stimulus allowing activation of downstream signalling pathways. Extracellular and intracellular RET domains are separated by a transmembrane domain [reviewed in 17]. To date, 4 members of the glial cell line-derived neurotrophic factor (GDNF) family, GDNF, artemin, neurturin and persephin have been identified as the soluble ligand members of the RET signalling complex. GDNF family members are distant members of the transforming growth factor-b (TGF-b) superfamily. In order to bind to RET, these GDNF proteins must first complex with their co-receptor. These ‘adapter’ molecules, known as the GDNF receptor a (GFRa) family, anchor to the cell membrane via a glycosyl-phosphatidyl-inositol linkage. To date, GFRa 1-4 have been identified and whilst all have preferential binding to one of the GDNF ligands, some cross-talk does occur. Thus, the multi-component complex of GDNF family member - GFRa family member and RET is generated, allowing RET dimerisation, autophosphorylation of the receptor and the induction of downstream intracellular signalling [18]. Typical of a tyrosine kinase, when the intracellular tyrosine residues of RET become phosphorylated, they generate docking sites that recruit adapter proteins such as SHC (binds to Y1062) and GRB2 (binds to Y1096) thus activating a number of downstream signalling pathways including the RAS mediated MAP Kinase pathway involved in mitogenesis and neuronal differentiation and the phosphatidylinositol 3-kinase (PI-3 kinase) pathway involved in cell motility, proliferation and survival [reviewed in 19].
Greater than 98% of families with MEN 2A have a germline gain-of-function RET mutation in one of 5 cysteine residues, either in RET exon 10 (codons 609, 611, 618 or 620) or exon 11 (codon 634) [20]. Mutations in non-cysteine residues at codons 768, 790, 791, 804 and 891 located in the intracellular domain have been reported at lower frequencies and are generally found predominantly in FMTC families. Two mutations have been correlated exclusively with the MEN 2B phenotype, specifically M918T in 95% of cases and A883F in 3% of cases. These mutations encode the catalytic site of RET and are thought to alter substrate specificity leading to the activation of inappropriate downstream signalling pathways by RET [reviewed in 19].
The transforming capacity of a number of the non-cysteine mutants have been shown to be reduced compared to that of the most common MEN 2A and 2B mutations, C634R and M918T respectively, suggesting a possible functional basis as to why patients with these germline mutations generally have disease restricted to the thyroid C-cells [21]. Mutations affecting cysteines associated with the MEN 2A / FMTC phenotype are believed to lead to dimerisation of the RET receptor independent of binding of the ligand-co-receptor complex as unpaired cysteines become available for the formation of intermolecular bonds [22].
The clustering of mutations in RET in MEN 2 patients has meant it has been relatively easy to establish screening programs for this syndrome. International, multi-centre studies have allowed genotype-phenotype correlations to be drawn, grouping phenotypes on a family-as-a-unit basis. Specifically, mutations in codon 634 have been associated with a higher risk of the presence of phaeos and hyperparathyroidism [20].
Multiple Endocrine Neoplasia Type 1 (MEN 1)
Clinical Features
The endocrine glands affected in Multiple Endocrine Neoplasia Type 1 (MEN 1;OMIM#131100) include the parathyroid glands (primary hyperparathyroidism but never parathyroid carcinoma) in 90-97% of patients, the duodenal and pancreatic endocrine tissues in 30-80% of patients and the anterior pituitary gland in 15-50% of cases [reviewed in 23]. Less commonly, tumours including thymic carcinoids, lipomas and benign adrenocortical and thyroid tumours may also be present. In contrast to MEN 2, phaeo would appear to occur as an atypical variant of MEN 1, usually occurring unilaterally and rarely malignant [reviewed in 24].
Criteria for the diagnosis of MEN 1 usually states that an individual must have at least 2 of the most commonly affected endocrine glands involved with a first degree relative having at least one of the lesions seen in MEN 1 [24]. The frequency of MEN 1 in the population has been estimated to be between 1 in 10 000 to 1 in 100 000, with penetrance approaching 100% by the age of 50 years [25]. Nearly 50% of MEN 1 patients succumb to their disease, with the most frequent cause of death in these patients being malignant pancreatic islet cell tumours followed by carcinoid tumours [26].
In Familial Isolated Hyperparathyroidism (FIHP; OMIM#145000), primary hyperparathyroidism occurs as the sole endocrinopathy. There is much debate in the literature as to whether FIHP is a distinct disease entity or is possibly a variant of MEN 1 in much the same way as FMTC is a variant of MEN 2A [27]. A further possibility is that FIHP, or a subset of FIHP, are variants of the Hyperparathyroidism-Jaw Tumour Syndrome (HPT-JT; OMIM#145001) [reviewed in 23]. Cloning of the HPT-JT gene should assist in elucidating the genetic origin of FIHP.
Molecular Determinants – MEN1, Menin
The MEN 1 gene was first linked to chromosome 11q13 in 1988, however it took nearly 10 more years for the gene to be identified by positional cloning [28, 29]. The MEN 1 gene spans over 9 kb and consists of 10 exons, the first exon being untranslated. It encodes a 610 amino acid (67 kDa) protein called menin located predominantly in the nucleus [30].
The lack of known functional motifs encoded by the menin sequence has proved a challenge for identifying the function of this protein. However, menin has recently been shown to interact with the AP1 transcription factor JunD, an inhibitor of cell growth, to repress JunD transcriptional activity [31]. Thus, if menin is mutant, it may lose its ability to interact with JunD, leading to cellular proliferation. Menin has also been shown to interact with Smad3, important in the TGF-b signalling pathway. Mutant menin may lead to inhibition of TGF-b signalling resulting in tumourigenesis [32]. Further, menin also interacts with nm23 (nonmetastatic 23) which has previously been implicated in growth, differentiation, development and the suppression of tumour metastasis [33]; with the NF-kB proteins p60, p52 and p65, inhibiting NF-kB mediated transcriptional activation [34]; and with Pem, a homeobox containing protein encoded by a placenta and embryonic expression gene [35]. The functional consequences of all of these menin interactions remain to be elucidated.
Predicted loss-of-function germline mutations (nonsense, frameshift and splice-site mutations predicted to truncate the protein) in MEN1 have been reported in between 60-90% of MEN 1 patients scattered throughout the entire coding region of the gene [reviewed in 36]. MEN 1-related tumours frequently display LOH at 11q13 (Knudson’s ‘second hit’) and further, tumours analysed from the Men1 heterozygous mutant mouse show loss of the wild-type Men1 allele [36]. Thus, there is strong evidence at the DNA level that MEN1 functions as a TSG. No clear correlations have been identified between the nature or position of mutations and phenotype [37].
Given that almost 50% of MEN 1 patients die as a result of MEN 1-related disease, the ability to identify these individuals at a young age by genetic screening may lead to decreased morbidity and mortality. However, unlike RET screening in MEN 2 families where knowledge of the carrier status can lead to prophylactic or early surgery that may avoid or cure thyroid cancer, mutation screening in MEN 1 patients cannot avoid or cure malignancy. At best, mutation screening in MEN 1 patients can assist clinical management and aid in life-planning decisions [24].
von Hippel-Lindau Disease (VHL)
Clinical Features
VHL (OMIM#193300) is a multi-system disorder with affected individuals at-risk of developing central nervous system haemangioblastomas, including retinal, spinal and cerebellar haemangiomas; clear cell renal carcinomas (RCC) which are the major cause of morbidity; phaeo and occasionally, extra-adrenal paragangliomas (PGLs) [reviewed in 38]. The birth incidence of VHL is believed to be in the range of 1 in 36 000 to 1 in 39 000 [39]. Expressivity of this disease varies greatly, with up to 50% of gene carriers developing only one feature of VHL, yet penetrance is said to be approaching complete by 65 years of age [reviewed in 38]. Clinically, VHL is classified according to tumour presentations, with Type I manifestations including RCC and CNS haemangioblastomas but no phaeos and Type II manifestations including all those of Type I in addition to phaeos. Further classification of Type II VHL can be made with Type IIA having low risk for RCC, Type IIB having high risk for RCC and Type IIC where the only manifestation of VHL is the presence of phaeos [reviewed in 40].
Molecular Determinants - VHL
Genetic heterogeneity has not been observed in VHL and a single gene for this syndrome, VHL, was identified in 1993 using positional cloning strategies [41]. Loss of the wild-type allele in VHL component tumours has been reported, consistent with a TSG function [42]. VHL maps to 3p25 and consists of only 3 exons encoding a 213 amino acid protein product pVHL, primarily residing in the cytoplasm but with the ability to shuttle to the nucleus [reviewed in 43]. A shorter protein also exists, due to an alternative translation initiation site. A wide spectrum of germline mutations have been identified in VHL patients including missense and nonsense point mutations, microdeletions, microinsertions, splice site, complex rearrangements (including inversions), whole gene and gross deletion [44]. Mutations are scattered along the entire gene, with the exception of the first 54 codons, and ‘hot-spots’ have been reported, most due to de novo events in unrelated families at hypermutable sequences such as CpG dinucleotides [45]. However, it should be noted that founder mutations have also been reported [46]. Given the heterogeneity of mutation type, it has recently been reported that by using a combination of fluorescence in situ hybridisation (FISH), Southern blotting and sequencing of the coding and flanking regions of VHL, mutations can be identified in nearly 100% of VHL families [44]. Germline mosaicism has been reported in VHL and is a factor to consider when analysing apparently sporadic presentations of this disease [47].
Genotype-phenotype correlations have been identified in VHL, specifically, mutations predicted to truncate pVHL and large deletions are associated with a lower risk of phaeo, ie VHL Type I, than missense mutations, especially those at codon 167 [48]. Further, one recent study suggests that the specific VHL mutation c.505T>C that is linked to a founder effect and predisposes to VHL Type IIA confers a risk of mortality no different to the general population compared to that of VHL patients with other mutations who have increased mortality [49]. Up to approximately 50% of phaeo only families have been reported to have a germline VHL mutation [50].
pVHL binds to elongin B via elongin C and this complex can then bind to cul2, a member of the cullin family [51]. VHL mutations have been shown to destabilise this complex and many of the mutations occur in a region encoding the amino acids of VHL critical for elongin C binding [52]. The pVHL-elongin-cul2 complex interacts with Rbx1 which facilitates polyubiquitination [53]. pVHL-elongin-cul2 complexes are thus ubiquitin ligases and have been shown to bind to and polyubiquinate the a subunit of HIF, a hypoxia inducible protein and a transcriptional activator, in the presence of oxygen, thus targeting HIF for degradation [reviewed in 43]. This process is stabilised by hypoxia where degradation of HIF-a is suppressed, leading to transcriptional activation of HIF target genes including genes involved in angiogenic pathways such as VEGF (vascular endothelial growth factor). This is consistent with the high level of vascularisation observed in many VHL associated tumours.
pVHL has also been shown to bind to fibronectin, allowing assembly of an extracellular fibronectin matrix, a function which is abolished by mutant VHL [54]. Specific VHL mutations associated with phaeo only families have recently been shown to encode mutant VHL that retains the ability to down-regulate HIF but loses the ability to promote fibronectin matrix assembly, suggesting a critical role for fibronectin matrix assembly in the development of VHL associated phaeo [55].
Cowden Syndrome (CS)
Clinical Features
CS (OMIM#158350) usually presents in the third decade, however there is considerable inter- and intra-family differences in expressivity of this syndrome. CS is characterised by the presence of hamartomas, non-neoplastic developmentally disorganised tumour-like tissue overgrowths, in multiple organ systems including the breast, thyroid, skin, gastrointestinal tract and central nervous system [56]. These hamartomas include trichilemmomas in 99% of CS patients, breast fibroadenomas in 70% of CS females, thyroid adenomas and multinodular goitre in 40-60% of patients and gastrointestinal polyps in 35-40%. Malignant breast cancer develops in 25-50% of CS females, thyroid cancer develops in 3-10% and endometrial cancer can also be associated with CS [reviewed in 57]. Additional non-malignant characteristics of CS include megencephaly or macrocephaly, genitourinary abnormalities and Lhermitte Duclos disease (dysplastic gangliocytoma of the cerebellum) that is sometimes associated with CS. An international CS consortium has been formed and operational criteria for the diagnosis of CS has been recommended [58]. Bannayan-Riley-Ruvalcaba (BRR) shows partial clinical overlap with CS, however whilst malignant lesions have been described in a small subset of BRR patients, it is unclear whether malignancy is formally part of this paediatric endocrine disorder [59].
Molecular Determinants – PTEN (MMAC1 / TEP1)
Three independent groups isolated the gene that was later identified as the gene for CS, hence the 3 different names for this gene – PTEN, Phosphatase and TENsin homologue deleted on chromsome Ten [60]; MMAC1, Mutated in Multiple Advanced Cancer 1 [61]; and TEP1, TGF-b-regulated and epithelial cell-enriched phosphatase [62]. PTEN was definitively established as the susceptibility gene for CS after germline nonsense and missense mutations were identified in 4 of 5 unrelated CS families [63].
PTEN has 9 exons encoding a 403 amino acid protein, residues 122-132 encoding the classic phosphatase core motif (I/V)HCXXGXXR(S/T)G. Of considerable interest, PTEN has a processed pseudogene located on chromosome 9p21 that shares greater than 98% homology with the coding region of PTEN, yet lacks PTEN’s initiating methionine [64]. For this reason, care must be taken for all PTEN mutation studies undertaken using cDNA to avoid inadvertent analysis of the pseudogene. Extensive homology to the cytoskeletal proteins tensin and auxillin is observed in PTEN’s NH2-terminal domain [reviewed in 57]. PTEN has been localised to the cytoplasm [62], however immunohistochemical studies of 2 component tumours of CS, breast and thyroid, have indicated a nuclear predominance [65, 66]. Upon reintroduction of wild-type PTEN into glioma cells endogenously mutant for PTEN, growth suppression was observed, providing strong evidence that PTEN was able to function as a TSG [67].
PTEN has been shown to act in the PI-3 kinase pathway as a 3-phosphatase, dephosphorylating phosphatidylinositol 3,4,5-triphosphate (Ptd-Ins(3,4,5)P3) to phosphatidyl-inositol 4,5-diphosphate (Ptd-Ins(4,5)P2) [68]. Ptd-Ins(3,4,5)P3 is a critical second messenger in the regulation of cell growth functioning to mediate growth factor induced activation of cell growth signalling [69]. Mutant PTEN leads to the accumulation of Ptd-Ins(3,4,5)P3 that activates the anti-apoptotic serine threonine kinase AKT [70]. Further to a role in apoptosis, PTEN has also been shown to cause cell cycle arrest in cells in the G1 phase, however whether this occurs via modulation of the phosphorylation levels of pRB is controversial [reviewed in 57]. It is possible that PTEN-induced growth suppression via different mechanisms may be tissue specific. Recently, there has been the suggestion that haploinsufficiency of PTEN may be sufficient to participate in tumourigenesis, at least in certain tissue types [71].
In addition to PTEN’s lipid phosphatase activity, PTEN also demonstrates in vitro phosphatase activity against protein and peptide substrates phosphorylated on threonine, serine and tyrosine residues, thus classifying PTEN as a dual specificity phosphatase [72]. In vitro, overexpression of PTEN negatively regulates cell migration, integrin-mediated cell spreading and the formation of focal adhesions, possibly via its interactions with focal adhesion kinase (FAK) [73]. Further, PTEN, like other TSGs including SMAD4 in JPS, may also have a role in the TGF-b signalling pathway [62].
Germline mutations have been identified in up to 81% of CS patients, scattered largely over the entire gene with the exception of exon 1 and including point missense and nonsense, intragenic deletions and insertions, deletion-insertions and splice site mutations. Further, LOH in PTEN mutation positive CS families has been described providing additional evidence for PTEN functioning as a TSG. Mutation clusters do occur, with the majority of mutations occurring in exon 5 where the PTPase core motif resides and also the largest exon, constituting 20% of the coding region. Many of the missense mutations reported in PTEN occur in the core motif, indicating the importance of this functional domain. Second mutation ‘hot-spots’ occur in exons 7 and 8 believed to encode potential tyrosine and serine phosphorylation sites [reviewed in 57]. The possibility of genetic heterogeneity in CS has been raised in a single study, however to date, no additional genes have been linked to this syndrome. Preliminary genotype-phenotype correlations in this syndrome in 35 CS patients have revealed trends towards an increased risk of developing breast abnormalities in the presence of a germline PTEN mutation [74], however smaller studies have not reported this phenomenon. It is possible that at least some of the different phenotypes observed in CS may be the result of different PTEN mutants functioning via different signalling pathways, either acting on phospholipid or protein / peptide substrates [72, 75]. Clinically useful genotype-phenotype correlations will require analysis of a larger cohort in the future. Still, effective DNA-based predictive screening programs have now been incorporated as part of the clinical management of CS patients.
Germline PTEN mutations have also been reported in 50-60% of patients with BRR [reviewed in 57]. Given that identical mutations have been reported to cause either CS or BRR, it is likely that additional genetic or epigenetic factors are present acting as modifier loci. To further support this theory, families have been reported with a single germline PTEN mutation in which both the CS and BRR phenotypes are expressed, with BRR most often occurring in the younger generation of these families.
Familial Paraganglioma and Phaeochromocytoma (PGL and Phaeo)
Clinical Features
As well as occurring as a component tumour in MEN 2, VHL, and rarely Neurofibromatosis Type 1 (NF1), phaeo can occur in conjunction with PGL, or PGL can also occur alone (OMIM#168000, #605373, #185470). Phaeos are neural crest derived, mostly catecholamine secreting tumours of the sympathoadrenal neuroendocrine system, arising in the chromaffin cells of the adrenal medulla. Approximately 90% of phaeos arise in the adrenal medulla, the remainder being located in the extra-adrenal paraganglia, with conflicting evidence as to whether the latter have a greater risk of malignancy [76].
Parasympathetic associated PGLs are tumours of the extra-adrenal paraganglion tissue but at times may be intra-abdominal (ie. extra-adrenal chromaffin cells) and classified as PGLs or extra-adrenal phaeos [reviewed in 77]. PGLs are highly vascularised tumours, usually located in the head and neck where they are generally slow growing and comprised of the neural-crest derived chief cells, The most common site for PGL is the carotid body that is an organ that functions to sense oxygen levels in the blood, stimulating the cardiopulmonary system in response to low oxygen levels, referred to as hypoxia [78]. Hyperplasia may be seen in the carotid body in conditions of chronic exposure to oxygen deprivation such as may occur at high altitude.
The penetrance of familial PGL would appear to be incomplete and age dependent, although considerable variability in age of onset does exist. ‘Generation skipping’ and inheritance of tumours through the paternal line in a subset of PGL families provided early phenotypic evidence for genomic imprinting in these families [79]. In genomic imprinting, the inheritance of the imprinted gene conforms to Mendelian principles, however whether or not the gene is functionally active depends upon the sex of the carrier parent.
Molecular Determinants – SDHB, SDHC and SDHD
Familial PGL displays genetic heterogeneity and 3 independent loci have been identified – PGL1 at 11q23, PGL2 at 11q13 and PGL3 at 1q21. Only one of these loci, PGL1, has shown evidence of being imprinted [reviewed in 78]. Recently, 3 genes encoding subunits of mitochondrial complex II (also referred to as succinate-ubiquinone oxidoreductase) have been shown to harbour disease associated germline mutations – SDHB mapping at 1p36.1-p35 and encoding a 30kDa iron sulphur protein [80], SDHC mapping at the PGL3 locus [81] and SDHD mapping at the PGL1 locus [82], encoding respectively the large and small subunits of cytochrome b. Germline mutation of SDHA causes Leigh Syndrome, a respiratory chain deficiency not associated with malignancy. The SDHC and SDHD encoded subunits anchor the SDHA and SDHB encoded subunits of mitochondrial complex II to the inner mitochondrial membrane. The mitochondrial complex II controls aerobic electron transport as part of the Krebs cycle and has a role in regulating oxygen sensing and signalling [83].
The first of these genes to be associated with familial PGL was SDHD, with the finding of germline missense and nonsense mutations in 4 families with familial PGL. Further, loss of the maternal allele has been identified in a subset of tumours from these families, hinting at a function for SDHD as a TSG [82]. Additional reports of mutations in all 4 exons of SDHD in familial PGL with or without phaeo have followed, one such report of 2 families with carotid body PGL occurring in conjunction with hearing loss [84-86]. A founder effect for the mutations D92Y and L139P has been shown to account for the inheritance of 94% of PGLs in 32 Dutch families [87]. Furthermore, SDHD mutation has been identified in 40% of Dutch patients (N=55) presenting with apparently sporadic PGL, the majority of these carrying the same mutation as those identified as having a founder effect. This raises the interesting possibility that these mutations may have a particularly low penetrance, although other possibilities including the masking of inheritance by imprinting and these sites being ‘hot-spots’ for de novo mutations cannot at present be excluded. The SDHD mutation R22X has been further studied, with the finding of complete loss of complex II enzymatic activity in homogenised tumour tissue. Further, gene expression studies of these tumours using immunohistochemistry and real-time PCR showed increased expression of angiogenic factors including VEGF [88]. Curiously, SDHD is not located in an imprinted genomic domain, and the mechanism of imprinting seen in PGL1 linked familial PGL remains to be elucidated.
To date, a single PGL3 linked family with non-chromaffin head and neck PGL has been reported with a germline mutation in SDHC that destroys the starting methionine [81]. Tumours from two affected individuals showed LOH at this locus, suggestive of a TSG function for SDHC. The disease inheritance pattern in this family showed no evidence of the imprinting seen in PGL1 linked families. Further, SDHB mutations have been identified in families with PGL and phaeo or small phaeo alone families, with an apparent ‘hot-spot’ evidenced by the finding of the R90X mutation in 3 of 4 unrelated families [80]. To determine whether this mutation truly accounts for phaeo only familes as well as familial PGL will require the analysis of additional, and multi-generational, families. Germline mutations in SDHB, SDHC and SDHD reported to date are reviewed in [77].
The finding of germline mutations in the subunits encoding the mitochondrial complex II in a neoplasia syndrome provides further evidence of the link between tumourigenesis and mitochondrial dysfunction. However, much remains to be elucidated in familial PGL, including the involvement of a possible fourth gene at the PGL2 locus and the explanation of the imprinting phenomenon seen in families with SDHD mutation.
Carney Complex (CNC)
Clinical features
Carney Complex (CNC; OMIM#160980) is characterised by spotty skin pigmentation (the most common clinical manifestation of CNC); multiple tumours including pituitary (growth hormone and prolactin producing adenomas) and testicular (primarily large-cell calcifying Sertoli cell tumours); and less commonly breast ductal adenoma and thyroid adenoma or carcinoma [reviewed in 57]. Furthermore, cardiac and other myxomas may be present in CNC as well as the adrenal lesion primary pigmented nodular adrenal disease (PPNAD) that can lead to atypical Cushing syndrome [89]. The extremely rare condition of multiple chondromatous hamartomas of the lung has also been reported in conjunction with CNC [90]. The life span of a patient with CNC is reduced, with the primary cause of death being heart or heart-related abnormalities [91]. Given the diversity, variable penetrance and expressivity of this condition, diagnosis of a CNC family can be difficult, however recommendations for diagnostic criteria and clinical screening have recently been established [91].
Molecular Determinants - PRKAR1A
As in JPS and LFS, genetic heterogeneity has proven to be a feature of CNC, with likely 3 loci involved. Germline mutations of PRKAR1A, mapped to 17q22-24 and encoding the type Iá regulatory subunit of protein kinase A (PKA), including nonsense, frameshift and splice site mutations, have been reported in a subset of CNC families and likely account for 50% of patients with CNC [92, 93]. Furthermore, loss of the wild-type allele has been identified in a subset of PRKAR1A mutation positive CNC component tumours, suggesting that this gene functions as a TSG in these tissues. The differences in expressivity and penetrance both within and between PRKAR1A mutation positive CNC families will likely be attributed to the presence of modifier genes [93]. Of note, a processed PRKAR1A pseudogene has been located on 1p21-p31 with 89% homology to the open reading frame of the expressed PRKAR1A [94].
PRKAR1A is a cAMP dependent protein kinase and the majority of mutations identified in CNC are predicted to generate truncated proteins lacking cAMP binding sites. If cAMP were unable to bind to PRKAR1A, the catalytic subunits of PKA would not be released to phosphorylate threonine and serine residues and would not be able to enter the nucleus to phosphorylate transcription factors regulating gene expression. The complex kinetics of the multimeric PKA enzymatic complex and its likely dysregulation in CNC remain to be elucidated in full, however, the identification of mutations in PRKAR1A associated with CNC constitute the first report of a likely downstream defect in the cAMP pathway [reviewed in 95].
A locus at 2p16 has also been linked to a subset of families with CNC, although to date, the gene has not been identified [reviewed in 57]. Still, some families with CNC do not appear to be either chromosome 2 or chromosome 17 linked, raising the possibility of yet a third locus involved in the pathogenesis of this syndrome. However, given the clinical overlap between CNC and other lentiginosis syndromes such as PJS, it is possible that some cases of CNC will be reclassified, perhaps with the benefit of molecular diagnostics, to one of these conditions showing phenotypic overlap [reviewed in 57].
Intestinal Cancer Syndromes:
In general, increased familial susceptibility to intestinal cancer is classified into subgroups based on the presence, or lack of, colorectal polyposis. The susceptibility loci of a number of these syndromes have recently been identified, including those for JPS, PJS and CS (discussed elsewhere in this review). FAP and the genes causing HNPCC are also discussed.
Familial Adenomatous Polyposis Syndrome (FAP)
Clinical Features
Patients with FAP (OMIM#175100) characteristically develop hundreds to thousands of adenomatous polyps throughout the colon and rectum during adolescence. These polyps are more commonly seen on the left side of the colon and in the rectum. Approximately 15% of patients have developed polyps by 10 years of age and 90% by age 30. Adenomatous polyps are benign, although some will progress to carcinoma, with the average age of detection of this malignancy in FAP patients being 35 [reviewed in 96]. These malignant tumours can show chromosomal instability and may behave aggressively [97]. Patients with FAP are also at-risk of extracolonic malignancies including papillary thyroid carcinoma, pancreatic adenocarcinoma and pre-malignant duodenal polyps. Other benign extra-colonic manifestations of FAP include desmoid tumours, osteomas, congenital hypertrophy of the retinal pigment epithelium (CHRPE) and epidermoid cysts. Gardner Syndrome is part of the FAP spectrum and is characterised by colorectal polyposis, osteomas, epidermoid cysts and skin fibromas. Turcot Syndrome, also known as Glioma-Polyposis Syndrome, is characterised by the association of colorectal polyps and primary central nervous system neoplasms. At least a subset of Turcot Syndrome can be classified as a FAP variant [98].
Molecular Determinants - APC
The gene for FAP was first mapped to chromosome 5 in 1987 and identified as the APC gene at 5q21 in 1991 [99, 100]. APC has 15 exons encoding a protein of 310 kD. Germline mutations described in APC occur most commonly in the first third of the gene and include small intragenic insertions and deletions causing frameshifts and point mutations, predicted to lead to a functionally inactive protein [99, 100]. A mutation cluster region has been identified in APC at codons 1286-1513 and this has been important in defining a variant on Knudson’s ‘2 hit’ hypothesis in that the type of second hit in tumours of FAP patients depends upon the site of the germline mutation. FAP patients with a germline mutation in the vicinity of codon 1300 generally acquire their second ‘hit’ by loss of the wild-type allele and suffer more severe disease, however FAP patients with germline mutations positioned elsewhere generally acquire a second ‘hit’ by a truncating mutation in the mutation cluster region [5]. This would suggest that the balance between lost C-terminal functions and retained N-terminal functions may be important [5]. These findings question the classification of APC as a classic TSG. Further, an attenuated FAP variant characterised by fewer colonic adenomas, less than 100, located predominantly in the proximal colon, and a later age of onset of colorectal cancer (CRC) has been reported and attributed to mutations nearer the 5’ (5’ to codon 158) or 3’ (3’ to codon 1596) ends of APC than those associated with the more classical FAP phenotype [101, 102].
A mutation at nucleotide 3920 of APC, I1307K, has been identified in 28% of Ashkenazim with a family history of CRC [103]. This mutation does not alter the function of APC by itself, but rather creates a small hypermutable tract (AAATAAAA to (A)8) that indirectly causes cancer predisposition by leading to somatic truncating mutations at adjacent sequence [103]. The lifetime risk of CRC in the general Ashkenazi population has been estimated at 9-15%, however for those Ashkenazim with I1307K, the risk is likely to be elevated to 18-30% [103].
APC has been shown to be involved in the Wnt signalling pathway, binding to b-catenin and preventing expression of the oncogene c-MYC that is often upregulated in colorectal tumours [104]. Recent evidence suggests that Wnt signalling may be an inhibitor of apoptosis [105]. Further, APC has also been shown to be critical for the maintenance of chromosomal stability. APC accumulates at the kinetochore during mitosis, however the mitotic spindles of mutant APC cells do not connect efficiently with the kinetochores, contributing to the chromosomal instability seen in CRC [106].
Hereditary Non-Polyposis Colon Cancer (HNPCC)
Clinical Features
HNPCC (OMIM#114500), also known as Lynch Syndrome, is thought to account for approximately 6% of all CRCs and as such is the most common hereditary form of CRC [107, reviewed in 108]. Penetrance of this syndrome is approximately 85-90% [108]. Unlike in FAP, there is a paucity of adenomatous colonic polyps and the CRCs seen in HNPCC are adenocarcinomas characterised by poor differentiation. HNPCC is often further classified based on the presence or absence of extracolonic malignancies. Type I has the features of an early age of onset of approximately 44 years, malignancy that occurs predominantly in the proximal colorectum (70%) and an excess of colonic malignancies. Type II has, in addition to these symptoms, carcinoma of the endometrium and other organs such as the stomach, ovary, pancreas, small bowel, biliary tract, skin, larynx, breast and haematological malignancies [reviewed in 107]. Some gender differences are apparent in HNPCC, with males having an increased overall cancer risk compared to females [109]. HNPCC can be difficult to recognise clinically given that the colorectal and extracolonic cancers may span quite a broad spectrum. Criteria for the diagnosis of HNPCC, generally known as the ‘Amsterdam criteria’ have been established and recently revised given the strong predisposition to malignancies other than colorectal in this syndrome [reviewed in 107; 108, 110]. Whilst being part of the FAP clinical spectrum, a subset of families with Turcot Syndrome (OMIM#276300) are also part of the HNPCC clinical spectrum [98]. Muir-Torre Syndrome (OMIM#158320) is another variant of HNPCC characterised by HNPCC-associated cancers and sebaceous adenomas.
Molecular Determinants – hMSH2, hMSH6, hMLH1, hPMS1 and hPMS2
In HNPCC, germline mutations have been identified in 5 genes that function as caretakers of the genome by DNA nucleotide mismatch repair, specifically hMSH2 (human mutS homologue 2) [111, 112], hMSH6 (also called GTBP) [113, 114], hMLH1 (human mutL homologue 1) [115, 116], and hPMS1 and hPMS2 (human postmeiotic segregation 1 and 2) [117]. Even so, a number of HNPCC and HNPCC-like families are not linked to mutations in one of these genes, indicating that other as yet unknown susceptibility loci exist for HNPCC, including gene mutations and likely polymorphisms of low penetrance [97].
Mutations of hMLH1 and hMSH2 are the most common seen in HNPCC [118]. Characteristic errors of replication known as microsatellite instability, are present in the DNA of cancers of affected patients as a result of the uncorrected mispairing of nucleotides and the consequent misalignment of DNA strands [119]. These manifest as insertions or deletions within poly(CA)10-30 and other simple repeat sequences. A subset of families with Turcot Syndrome have been reported to harbour germline mutations in hMLH1 and hPMS2 [98]. The Muir-Torre Syndrome has been associated with germline mutation of hMSH2 [120].
In HNPCC, affected patients generally have inactivation of one copy of a mismatch repair gene, with corresponding loss of the wild-type allele in the tumour, thus the function of these genes resembles that of TSGs, in that functional loss of both alleles would seem to be required for tumourigenesis [121]. The discovery of these genes has provided evidence for the presence of a mutator phenotype appearing early in tumourigenic pathways, resulting in intrinsic genetic instability [122].
Juvenile Polyposis Syndrome (JPS)
Clinical Features
Up to 2% of children and adolescents develop juvenile polyps, however only a small proportion of them occur as part of JPS (OMIM#174900). While sporadic juvenile polyps are usually solitary and only rarely become malignant, the polyps seen in JPS are multiple, occurring throughout the gastrointestinal tract and are usually located in the colon but sometimes in the stomach and small bowel. JPS polyps have an inflammatory stroma with abundant lamina propria and are set apart from the PJS polyps in that they do not contain smooth muscle [123]. The risk of colorectal and other gastrointestinal malignancy is increased in JPS patients [123]. Extra-colonic manifestations of JPS have been reported including pancreatic and stomach cancers, congenital heart disease, bony swellings, cleft lip and palate and macrocephaly, however it remains to be determined whether all of these abnormalities are part of the JPS disease spectrum [124]. Not infrequently, the diagnosis of JPS is made after the clinical exclusion of other hamartoma polyposis syndromes such as CS or BRR, raising the possibility of misdiagnosis of this syndrome.
Molecular Determinants – SMAD4 (MADH4) and BMPR1A
JPS is a syndrome that displays genetic heterogeneity. To date, germline mutation of 3 genes have been reported to cause JPS - SMAD4 (SMA- and MAD- related protein 4, also known as DPC4, homozygously deleted in pancreatic cancer, locus 4), PTEN, and most recently BMPR1A (bone morphogenetic protein receptor 1A) however, it is likely that germline mutations in only 2 of these genes, SMAD4 and BMPR1A are truly linked to JPS.
JPS and CS are often grouped together along with PJS and CNC as the major hamartomatous polyposis syndromes with a neoplastic component. However, while gastrointestinal polyps are diagnostic of JPS, they are less frequently found in CS. The possibility that JPS and CS are allelic variants of the one syndrome has been extensively explored [reviewed in 57]. It is likely that some of the PTEN-linked apparent JPS patients are in fact cases of CS or BRR and further, that a molecular finding of PTEN mutation should be considered as diagnostic of these syndromes [125].
Germline mutations in SMAD4 predicted to generate a truncated SMAD4 protein disrupting the COOH-terminus, have been identified in a subset of JPS [126, 127]. Thus, SMAD4 would appear to be functioning as a TSG. SMAD4 maps to 18q21.1, and consists of 11 exons encoding a 552 amino acid protein with a highly conserved COOH-terminus that is a cytoplasmic mediator in the TGF-b signalling pathway [126]. SMAD4 forms homotrimers that complex with other SMAD proteins (SMAD1, SMAD5 and possibly SMAD8) at the cell surface by activation of TGF-b or related ligands that act on the TGF-b family transmembrane serine-threonine kinase receptors, phosphorylating the SMAD proteins so allowing them to complex. These SMAD complexes migrate to the nucleus where they act as transcriptional regulators by associating with DNA binding proteins. Without SMAD4’s intact COOH-terminus these SMAD complexes may not be able to form, thus leading to loss of TGF-b signalling [128].
A 4 base pair deletion, 1372-1375delACAG, in exon 9 of SMAD4 has been shown to be present in approximately 25% of JPS patients, even though a founder effect has not been demonstrated indicating that this site is possibly a mutational hotspot and may contribute to a high penetrance phenotype [129]. Clearly, this defines a molecular subgroup of JPS patients. However, germline mutation of SMAD4 has been suggested to account for only the minority of cases of JPS and other SMAD family members would not appear to be responsible for JPS [130].
An additional gene in the TGF-b superfamily, bone morphogenetic protein receptor 1A (BMPR1A), has recently been identified to be mutated in the germline in between 40 – 100% of JPS families without germline mutation of SMAD4 [131, 132]. The predominantly frameshift, nonsense point mutations and splice site mutations reported in BMPR1A in JPS patients are predicted to encode truncated receptors, leading to loss of BMP-mediated intracellular signalling [131, 132]. In addition, loss of the wild-type allele has been reported in a subset of BMPR1A mutation positive JPS-associated tumours, providing further evidence that BMPR1A likely functions as a TSG, perhaps like SMAD4, also having a gatekeeper function [132].
BMPR1A has 11 exons that encode a serine-threonine kinase type 1 receptor that mediates bone morphogenetic protein (BMP) signalling through SMAD4 as described above by phosphorylating SMAD family members that allow them to associate with cytoplasmic SMAD4. Curiously, this gene maps nearby PTEN at 10q21-q22, meaning that 2 genes that cause hamartomatous polyposis syndromes are tightly linked on the long arm of chromosome 10. Still, SMAD4 and BMPR1A likely do not account for all of the mutations present in JPS and it is possible that at least one other gene should exist to account for the genetic heterogeneity apparent in this condition [132]. Nonetheless, detection of a SMAD4 or BMPR1A mutation should be considered as diagnostic of JPS [132].
JPS-associated polyps have provided a model system for exploration of the theory of a third class of functionality of cancer genes. In addition to the caretakers and gatekeepers, it has been suggested that some genes may function as ‘landscapers’ [1]. A number of TSGs including TP53, RB1 and APC, function directly as gatekeepers to prevent uncontrolled cell growth. As described earlier, other genes are classified as caretakers and function less directly to achieve the same objective, including the DNA mismatch repair genes mutated in HNPCC. However some genes may function in a tumour’s microenvironment to influence the development of neoplastic cells and this postulated third class of genes have been called the ‘landscapers’.
The JPS polyp is a mix of mesenchymal and inflammatory stromal cells that entrap normal epithelial cells, often forming dilated cysts. Initially, the epithelial cells within and surrounding the JPS polyp are not neoplastic, yet they are at an increased risk of neoplasia. This raises the interesting question of whether the increased cancer susceptibility of these cells in JPS patients could be due to an abnormal stromal environment [1]. Recent studies would suggest that at least in SMAD4-related JPS, this would not appear to be the case given that biallelic inactivation of SMAD4 was identified in both the epthelium and some stromal cells in these tumours, providing evidence suggestive of a clonal origin [133]. It is likely then that in JPS, SMAD4 functions as a gatekeeper TSG in juvenile polyps [133]. However the functional classification of BMPR1A and as yet unknown genes accounting for the remaining genetic heterogeneity observed in JPS remains to be determined.
Peutz Jeghers Syndrome (PJS)
Clinical Features
The overall incidence of malignancy in PJS (OMIM#175200) is believed to be 20-50% and may affect a number of tissues including the gastrointestinal tract, pancreas, breast, gonads (a type of Sertoli cell tumour in the male testis are identical to those seen in CNC and are unique to these 2 syndromes), uterus and cervix, as well as non-malignant lesions in all of these tissues [reviewed in 57]. Benign pigmentation of the skin and mucosa is also apparent in PJS, often leading to this syndrome being classified with the other lentiginosis syndromes – CNC and BRR. Gatrointestinal malignancy is perhaps the definitive malignancy in PJS, albeit at a lower rate than is seen in either FAP or HNPCC, and a progressive sequence from hamartoma to adenoma to carcinoma has been proposed based on the adenoma – carcinoma model for colorectal malignancy [134]. The PJS gastrointestinal polyps are unique when compared to those found in the other hamartoma syndromes in that they contain a characteristic smooth muscle component infiltrating the connective tissue core in a branching pattern [reviewed in 135]. They are found as both solitary lesions or in large clusters that are most commonly located in the jejunum but can be found throughout the gastrointestinal tract. In addition to this typical ‘PJS polyp’, adenomatous and hyperplastic polyps and mixtures of these histologies have also been reported [135].
Molecular Determinants – STK11 (LKB1)
A combination of the whole genome scan technique comparative genomic hybridisation that can be used to assess copy number changes in tumour tissue, LOH studies in DNA from PJS polyps and linkage analysis localised the susceptibility locus for PJS to 19p [136]. One year later, the PJS gene was identified at 19p13.3 by two independent groups, one naming the gene STK11 (for serine threonine kinase 11) and the other keeping an earlier name given to the then unlocalised and uncharacterised gene LKB1 [137, 138]. STK11 contains 9 exons transcribed in a telomeric to centromeric direction and encodes a novel 433 amino acid serine threonine kinase. Its 433 amino acid residues display almost 84% homology with XEEK1 (named for Xenopus egg and embryo kinase 1), a Xenopus cytosolic serine-threonine protein kinase. Of note, a second locus for PJS, possibly accounting for up to 30% of cases of this disease and conferring a high risk for proximal biliary adenocarcinoma, has been identified at 19q13.4 [reviewed in 57].
Large differences in STK11 germline mutation frequencies are reported in PJS cohorts from 10 – 100% which could be due to a number of factors including genetic heterogeneity, differential diagnosis, mutation detection scanning methods or geographical bias [reviewed in 57]. Mutational ‘hot-spots’ are apparent at codon 51-84 of exon 1 as well as in exon 7. The majority of mutations are predicted to abrogate the kinase activity of STK11, generating proteins with incomplete catalytic domains. In addition, given the earlier LOH studies that suggested loss of the wild-type disease allele in PJS polyps, and later studies showing allelic imbalance at the STK11 locus in other PJS tumours [139] it would appear that STK11 is functioning as a TSG. As such, STK11 is the first example of a susceptibility gene for a cancer syndrome to function by inactivation of its kinase activity [137]. This is in contrast to the activation of function seen in oncogenes mutated in the germline in familial cancer behaving as protein kinases including RET (MEN 2), MET (familial renal papillary cancer) and CDK4 (subset of FMM). Further, LOH and mutation analysis of STK11 in hamartomas and adenocarcinomas from PJS patients has provided evidence for STK11 acting as an early gatekeeper, regulating the development of PJS hamartomas that are likely the premalignant precursors of adenocarcinoma [140]. Definitive proof of a hamartoma-carcinoma sequence in PJS will however require further analyses.
A nuclear localisation signal has been identified in the mouse homologue, Stk11, and wild-type STK11 shows both nuclear and cytoplasmic localisation. Residues 43-88 are thought to be necessary for nuclear targeting of STK11 [141, 142]. Critical for the kinase function and growth suppression of STK11 are residues 1-346, with a deletion mutant of 1-310 displaying lost kinase activity [141, 142]. It has been proposed that STK11 functions as a growth suppressor at the level of a G0/G1 checkpoint rather than as a regulator of apoptosis [142]. Further, STK11 has been shown to bind to and regulate the brahma-related gene 1 (Brg1), that functions to regulate cell cycle progression [143]. Recent experiments in primary mouse embryonic fibroblasts taken from 8.5 day mouse embryos with targeted disruptions of Stk11 have shown increased VEGF expression, suggesting that mutant STK11 may lead to an increased angiogenic potential in some cell types [144]. Thus, STK11 would also appear to have a role in the VEGF signalling pathway.
Breast and Ovarian Cancer Syndromes:
Carcinoma of the breast is the most common neoplasia in Western females with a mean incidence of 10%. Between 5-10% of female breast cancers are thought to be of a hereditary nature, therefore a positive family history is one of the highest risk factors for disease. Given the high risk of sporadic breast cancer in the general population, for a family to be classified as having familial breast cancer the presence of 3 or more affected individuals is generally required. Hereditary breast cancer may occur in a number of presentations including: as the sole malignancy; in conjunction with other tumours including ovarian cancer; in both females and males; or as a component tumour of multi-tumour syndromes including LFS (discussed in this section) or CS, PJS or Ataxia Telangiectasia (A-T) (discussed elsewhere in this review). Additional genes to those currently known are likely to be linked to familial breast cancer.
BRCA1-Associated Syndrome
Clinical Features
Individuals with early age of onset (pre-menopausal) breast tumours, and / or ovarian tumours in either themselves or close family members are likely to be part of a BRCA1 linked breast cancer family (OMIM#113705). These breast tumours are often estrogen receptor negative, have a high mitotic index and somatic mutation of TP53, all suggesting an aggressive tumour phenotype [reviewed in 145].
Molecular Determinants – BRCA1
The first susceptibility locus for early-onset familial breast cancer was mapped to 17q21 in 1990 and the gene BRCA1 identified in 1994 using positional cloning methodologies [146]. BRCA1 has 24 exons, 22 of which are coding, with exon 11 constituting the majority of the coding region, so is amongst one of the larger genes associated with familial cancer syndromes. Germline mutations of BRCA1 have been identified in individuals with familial breast and ovarian cancer, including point missense and nonsense mutations, intragenic deletions and insertions and splice site mutations, scattered along the entirety of the gene, the majority of which are predicted to cause a truncated protein [147]. Deleterious missense mutations are generally located in conserved regions of the gene, indicating that these regions likely encode important functional domains. Allelic loss at 17q12-21 of the wild-type chromosome has been observed in familial breast and ovarian cancer tumours [148]. Further, introduction of wild-type BRCA1 into breast and ovarian cancer cell lines has been shown to inhibit growth in vitro, providing additional evidence that BRCA1 functions as a TSG [149].
The risk of BRCA1 mutation carriers developing breast cancer by the age of 70 has been estimated at greater than 80% and the risk of developing ovarian cancer at greater than 40% by the same age [150]. However, specific BRCA1 mutations, such as the 185delAG and 5382insC founder mutations seen in the Ashkenazi Jewish population may incur lower risks of developing these tumours [151].
BRCA1 encodes an acid nuclear phosphoprotein of 220 kDa with most studies identifying the full length protein in nuclear foci of epithelial cells and a splice variant, BRCA1 delta 11b, likely being cytoplasmic. A zinc finger motif has been identified at the 5’ end of BRCA1 [reviewed in 145]. Additional domains encoded by BRCA1 include the BARD1 (BRCA1-associated Ring domain protein 1) binding domain, RAD51 binding domain, BRCT (BRCA1 C-terminal) domain and granins homology domain. It is likely that BRCA1, may function as a caretaker involved in DNA repair. Evidence for this is provided by the identification of a physical interaction between BRCA1 and RAD51, the latter of which has been directly implicated in DNA repair by being critical for DNA recombination and double-stranded DNA break repair [152].
BRCA2-Associated Syndrome
Clinical Features
In addition to female breast cancer, males in BRCA2 linked breast cancer families (OMIM#600185) are at an increased risk of developing breast cancer. Amongst other cancers, prostate cancer would also appear to be over-represented in these families, as is pancreatic cancer, malignant melanoma, colon cancer and to a lesser extent than in BRCA1 associated families, ovarian cancer [153].
Molecular Determinants – BRCA2
BRCA2 was localised to 13q12-13 in 1994 after a genomic linkage scan of 15 families with familial breast cancer who were unlinked to the BRCA1 locus at 17q21 [154]. Wooster and colleagues noted that whilst families linked to this locus had a high risk of developing breast cancer, they did not appear to have as great a risk of developing ovarian cancer as those members of BRCA1-linked families [154]. Isolation of BRCA2 was achieved in 1995 with the identification of germline mutations in breast cancer families [155, 156]. Loss of the wild-type allele has been reported in a subset of BRCA2-linked families, suggesting that BRCA2 functions as a TSG [157].
BRCA2 has 27 coding exons, with exons 10 and 11 being the largest, and encodes a nuclear protein of 390 kDa [reviewed in 145]. Additional familial cancers have been associated with BRCA2 germline mutations including pancreatic carcinoma [158]. The risk of BRCA2 mutation carriers developing breast cancer by the age of 70 years is approximately 84%, with a lower risk of developing ovarian cancer than BRCA1 mutation carriers [159]. Further, the majority of families with both female and male breast cancer are due to mutation of BRCA2 [159].
Mutations in BRCA2 with a reduced penetrance have been identified in the Ashkenazim including 6174delT suggesting a founder effect [151]. A further BRCA2 mutation, 999del5, with apparent relatively low risk of developing breast cancer has been identified in the majority of Icelandic families with a positive history of breast cancer and has also been found associated with the development of male breast cancer [160]. Most BRCA1 and BRCA2 mutations are listed on The Breast Cancer Information Core (BIC) database ( http://www.nhgri.nih.gov/Intramural_research/Lab_transfer/Bic/index.html).
The BRCA2 protein contains 8 copies of a 30-80 amino acid BCR repeats encoded by exon 11 that have been shown to be required for binding to RAD51, this interaction then being critical for cellular response to DNA damage [161]. BRCA2 has also been shown to participate, along with BRCA1 and RAD51 in a DNA-damage response pathway [162]. Like BRCA1, BRCA2 has homology to the granin family of proteins [163].
Li-Fraumeni Syndrome (LFS)
Clinical Features
LFS (OMIM#151623) was first defined after observing familial clustering of certain types of malignancies including early onset breast cancer, soft-tissue sarcomas, brain tumours, adrenocortical tumours and leukaemia [164]. Criteria for classic LFS have been described as: presence of bone or soft tissue sarcoma presenting at less than 45 years of age in an individual henceforth described as the proband; presence of other cancers in first degree relatives of the proband presenting at less than 45 years of age; and one first or second degree relative of the proband in the same familial line presenting with cancer before 45 years or sarcoma at any age, however a number of LFS families do not conform to this classic definition [reviewed in 165].
Molecular Determinants – TP53, hCHK2 TP53 has often been described as the gene most commonly mutated in sporadic human cancers. It was this observation, rather than positional cloning efforts, that led to the identification of mutations in TP53 in the germline of patients with LFS [166, 167]. TP53 is located on chromosome 17p13 and has 11 exons that encode a 53 kDa nuclear phosphoprotein. Highly penetrant germline mutations have been reported throughout the gene associated with LFS, with the majority of mutations occurring between exons 5 and 8 [168]. TP53 encodes a number of conserved regions including SV40 large tumour antigen binding sites, a nuclear localisation signal and several phosphorylation sites, all important for normal function of the wild-type protein [reviewed in 165]. When mammalian cells are exposed to DNA damaging agents, p53 acts as a transcription factor for genes that induce cell cycle arrest or apoptosis, mediating arrest in the G1 phase of the cell cycle [169]. Transcriptional targets of p53 include mdm-2, BAX, GADD45 and p21 [reviewed in 165]. Introduction of wild-type p53 into cell lines that have lost functional p53 causes growth arrest or induces apoptosis, most likely by arresting cells in G1, but p53 would also seem to be implicated in cell cycle regulation at the G2 checkpoint [170, 171].
A second gene, hCHK2 (checkpoint kinase 2) has recently been identified as another susceptibility gene for LFS [172]. hCHK2 encodes a kinase that is the human homologue of the yeast Cds1 and Rad53 G2 checkpoint genes, and is phosphorylated in an ATM-dependent manner in response to DNA damage [173, 174]. CHK2 has been shown to directly phosphorylate p53, indicating a role for this gene in p53 regulation after DNA damage [175, 176]. The forkhead homology domain of CHK2 is involved in protein-phosphoprotein interactions that are required for activation of the yeast homologue Rad53 in response to DNA damage [177]. A missense mutation within this domain was identified in a patient with LFS [172]. A number of the mutations reported thus far in hCHK2 have been shown to result in either loss of hCHK2 kinase activity, or show reduced kinase activity with an inability to be phosphorylated at an ATM-dependent phosphorylation site and cannot be activated in response to DNA damage induced by gamma radiation [178].
Skin Carcinoma Syndromes:
Possibly because our skin is our largest organ, skin cancer is one of the most common malignancies. Familial skin cancer may represent in the order of 1% of all skin cancers [179].
Familial Malignant Melanoma (FMM)
Clinical Features
FMM (OMIM#155601) is a malignancy arising in the melanocytes, cells of neural crest origin located at the junction between the epidermal and dermal layers of the skin and function to produce melanin to help protect the skin from ultraviolet radiation. FMM is thought to represent 10% of cases of melanoma. Criteria include a younger than average age of onset, the presence of multiple primary melanomas and sometimes but not always, the presence of multiple, atypical moles known as dysplastic nevi [reviewed in 180]. An increased risk of gastrointestinal cancers, including pancreatic carcinomas, has been reported in a subset of patients with FMM [181]. The risk of developing FMM if a susceptibility gene has been inherited has been estimated at approximately 50% by 50 years of age [182]. The variable expressivity seen in familial melanoma kindreds can in part be explained by the interplay between the environmental exposure to ultraviolet radiation and the inheritance of a susceptibility gene. Melanoma can occur as a component tumour in other hereditary syndromes including XP, LFS, Retinoblastoma and HNPCC [183].
Molecular Determinants –CDKN2A ( p16) and CDK4
FMM displays genetic heterogeneity, with to date, 2 genes identified as susceptibility loci that account for the minority of FMM cases. The first of the genes to be isolated was CDKN2A, cyclin-dependent kinase inhibitor 2A, localised to chromosome 9p21 [184, 185]. Mutations identified were predicted to cause loss of function of the CDKN2A gene product p16. A number of families showed 9p21 linkage without mutation of the CDKN2A coding region, and at least a subset of these have subsequently been shown to have a mutation in the 5’ UTR of CDKN2A, that generates a novel translation initiation codon decreasing translation from the wild-type AUG [186]. It has been suggested that approximately 40% of investigated melanoma kindreds have CDKN2A germline mutation [183]. Recently, evidence has also been provided of a founder effect in the French population of the CDKN2A mutation G101W in patients with apparently sporadic melanoma [187]. A subset of families with germline CDKN2A mutations have an increased risk of additional cancers, especially pancreatic carcinoma [reviewed in 188].
The second of these genes to be identified in a small proportion of families was CDK4 mapping to 12q14 with mutation of exon 2 [189]. CDK4 forms complexes with D-type cyclins, a requirement for cells to pass through the G1 cell cycle checkpoint into S phase. CDK4-cyclin D complexes contribute to the phosphorylation of the retinoblastoma protein, leading to release of E2F transcription factors that function to activate the transcription of genes involved in DNA synthesis. p16 binds to the cyclin-dependent kinases CDK4 and CDK6 known to have a role in cell cycle regulation, inhibiting their kinase activity. When p16 binds to CDK4, it prevents the formation of the CDK4-cyclin D complex, acting to arrest cells in G1, thus inhibiting cell division by disruption of the cyclin-dependent kinase / cyclin D growth regulatory pathway. Functional studies of inactivating p16 mutants have shown in the majority of mutants studied, impairment of binding to CDK4 leading to unchecked cell growth providing evidence of a role for p16 as a TSG [190, 191]. Further, reintroduction of wild-type p16 into p16 mutant melanoma cell lines led to growth suppression [192]. CDK4 mutants associated with FMM are resistant to p16 binding, thus are resistant to normal p16 inhibition of cell growth [189]. Therefore, mutant CDK4 functions as an oncogene in that its function is as a growth promoter. CDK4, along with RET in MEN 2 and MET in HPRCC constitute the only proto-oncogenes implicated as inherited susceptibility loci in familial cancer.
Clearly, cell-cycle genes that function at the G1/S checkpoint, have a role in the pathogenesis of FMM. It is possible that other genes involved in regulation of the cell cycle may also be implicated as susceptibility loci for FMM.
Nevoid Basal Cell Carcinoma Syndrome (NBCC, Gorlin Syndrome)
Clinical Features
Nevoid Basal Cell Carcinoma Syndrome (NBCC, Gorlin Syndrome; OMIM#109400), is the most common of the inherited skin malignancies, with one UK study identifying a prevalence of 1 in 56 000 and a high rate of new mutations [193]. NBCC is characterised by the development of basal cell carcinomas, from few to over one thousand, in the teenage years on the face, upper trunk and neck, the development of which would appear to be correlated with the amount of ultraviolet exposure. Additional neoplasms seen in affected patients include medulloblastoma and meningioma. Further developmental abnormalities such as odontogenic keratocysts, pits of the palms and soles and a variety of skeletal abnormalities, including a Marfanoid habitus, are also seen.
Molecular Determinants – PTC
The human homologue of Drosophila patched, PTC, mapping to 9q22.3 has been identified as the susceptibility gene for NBCC, being shown to contain germline mutations of a truncating nature in NBCC families [194, 195]. Mutations have been identified throughout the gene, however no clear genotype-phenotype correlations have been determined [196]. LOH has been identified at this locus in familial BCCs, providing evidence that this gene functions as a TSG [194]. A role for PTC has recently been proposed as a participant in the G2/M checkpoint to prevent mitotic progression by interacting with cyclin B1 and regulating the localisation of M-phase promoting factor, a universal cell cycle regulatory complex [197]. Thus, PTC joins proteins such as p53 and pRB as negative regulators of cell division.
The Neurofibromatoses:
The neurofibromatoses are classified as phakomatoses along with Tuberous Sclerosis Complex (TSC) and VHL (discussed elsewhere). They consist of two distinct syndromes with a degree of phenotypic overlap - neurofibromatois type 1 (NF1) and neurofibromatosis type 2 (NF2). The mapping of 2 separate genes for these conditions has clearly defined them as separate entities. Unlike many of the other familial cancer syndromes, genetic heterogeneity has not been reported for either condition. Both NF1 and NF2 can occur in mosaic forms [198].
Neurofibromatosis Type 1 (NF1)
Clinical Features
NF1 (OMIM#162200), previously called von Recklinghausen Disease, is a relatively common disease with a frequency of 1 in 2190 to 7800 people that is characterised primarily by disorders of cells derived from the neural crest, the most common of these being neurofibromas (benign peripheral nerve sheath tumours) [199]. Café-au-lait spots are present in approximately 95% of adults with NF1. NF1 patients have an increased risk of developing malignancies including neurofibrosarcoma, astrocytomas, phaeos (in 5% of affected individuals), melanoma, rhabdomyosarcoma and chronic myeloid leukaemias (CMLs) [200]. While having relatively mild symptoms, affected individuals have a reduced life span due to the increased risk of malignancy [201]. The age of onset in this condition is variable, as is expression, however Lisch nodules (benign hamartomas of melanocytic origin on the iris) begin to appear during childhood and are eventually present in 100% of affected adults [200].
Molecular Determinants – NF1, Neurofibromim
The gene for NF1 was one of the first to be identified amongst the familial cancer syndromes by positional cloning strategies, mapping to chromosome 17q11.2 [202, 203]. The mutation rate of the NF1 gene is one of the highest known, with approximately 50% of cases predicted to be due to de novo mutation. Thus the NF1 gene represents a mutational ‘hot-spot’ in the human genome. NF1 is extremely large, consisting of at least 59 exons spanning approximately 300 kb of genomic DNA and containing 3 smaller genes within exon 1. The large size of this gene has made mutation scanning and hence the identification of genotype-phenotype correlations, difficult. A further complication of genetic analysis of NF1 is the presence of a number of pseudogenes located on 7 different chromosomes [200]. Mutations identified are generally predicted to truncate the protein, but also include total gene deletion [204]. Further, loss of the wild-type NF1 allele has been identified in NF1-associated tumours, thus supporting a role for NF1 as a TSG [205] Due to the accuracy of clinical diagnosis at a relatively young age and the difficulties of analysing the NF1 gene, molecular diagnostics do not play a huge part in the management of this syndrome.
The gene product of NF1 is neurofibromin that has been localised to the cytoplasmic microtubules and shares a region of homology with the catalytic domain of the guanosine diphosphate GTPase activating protein (GAP). Neurofibromin has been shown to function as a GAP for p21-RAS, that is it catalyses the conversion of GTP-bound p21-Ras to inactive guanosine diphosphate (GDP) p21-Ras. Many NF1-related tumours demonstrate elevated levels of Ras-GTP, most likely due to loss of functional neurofibromin [206]. Thus, neurofibromin would appear to function as a negative regulator of RAS-mediated cellular proliferation.
Neurofibromatosis Type 2 (NF2)
Clinical Features
NF2 (OMIM#101000) is also referred to as familial schwannomatosis. Schwannomas are neurofibroma-like tumours, hence some of the confusion in the clinical distinction between NF1 and NF2 [207]. In a study of the UK population, the birth incidence of NF2 has been estimated to be approximately 1 in 40 000 people [208], however considerable variability does exist in this estimation, depending upon the country of origin [reviewed in 209]. The hallmark malignancy seen in NF2 is bilateral vestibular schwannoma (acoustic neuromas), with other tumours including meningioma (the second most characteristic tumour of NF2), spinal tumours and skin tumours. Schwannomas are encapsulated tumours of pure Schwann cells growing around the nerve and can occur at any location of the body where there are nerves with Schwann cells. Non-tumour presentations of NF2 include hearing loss, retinal hamartoma and cataracts. NF2 displays variable age of onset, with most affected individuals presenting in their second to third decade. However, clinical variability is seen in this syndrome, with two distinct groupings of NF2 patients – ‘Gardner-type’ which is a later onset mild form with few associated tumours, and ‘Wishart-type’ which is a more severe form with earlier age of onset and multiple tumours. The penetrance of NF2 is extremely high, with greater than 95% of gene carriers presenting by the age of 50 years [reviewed in 179]. Recommendations have been suggested to assist in the clinical differentiation of NF1 and NF2 [reviewed in 179].
Molecular Determinants – NF2, Merlin/Schwannomin
The gene for NF2 has been mapped to 22q12 using positional cloning strategies [210, 211]. Approximately half of NF2 patients do not have a family history of disease and it is believed that these individuals represent de novo mutation of NF2 or alternatively mosaicism [208, 212]. NF2 is a large gene made up of 17 exons distributed over approximately 90 kb with a first exon of 32 kb [213]. The majority of mutations are thought to encode for truncated proteins, including substantial deletions, some encompassing the entire NF2 gene, however there are no real ‘hot-spots’ for mutation [213]. Further, loss of the wild-type NF2 allele in tumours from NF2 patients is consistent with a function for NF2 as a TSG. Evidence from a large genotype-phenotype study has confirmed earlier suggestions that mutations likely to truncate the NF2 protein are associated with more severe disease and an earlier age of onset [214].
The NF2 gene encodes a protein called merlin, named for its similarity to three known proteins in the ERM family (merlin = moesin, ezrin, radixin-like protein), and is also known as schwannomin. Novel splice variants have been identified that are both developmentally regulated, tissue specific and are targeted to specific subcellular localisations [215]. Merlin has been shown to directly interact with the actin cytoskeleton and carries out its tumour suppressor function by helping to maintain normal cytoskeletal organisation, impairing cell adhesion, motility and spreading properties [216]. Recent evidence has shown that this growth inhibitory function of merlin relies on interaction with the transmembrane protein CD44 [217].
Tuberous Sclerosis Complex (TSC)
Clinical Features
TSC (OMIM#191100) is characterised by the presence of hamartomas in multiple organs, primarily the skin, heart, kidney and brain, and is often associated with learning disabilities, particularly autism, rhabdomyomas, and epilepsy. The majority of neoplasms seen in TSC are benign, however giant cell astrocytoma and RCC have been reported in TSC, classifying TSC, perhaps more tenuously than the other syndromes discussed, as one of the familial cancer syndromes [179]. The penetrance of this syndrome is high (approximately 95%) and de novo mutations are believed to account for 65-85% of new patients [218]. Diagnostic criteria for TSC have recently been revised [219].
Molecular Determinants – TSC1 (hamartin) and TSC2 (tuberin)
TSC displays genetic heterogeneity with 2 genes being linked to this condition, the first in 1993 is TSC2 mapping to 16p13 [220] and the second, TSC1 was mapped to 9q34 in 1997, even though linkage to this locus had been established some time prior [221]. TSC2 is a large gene with at least 41 exons spanning approximately 45 kb of genomic DNA and encodes the protein tuberin. TSC1 contains 23 exons spanning approximately 40 kb of genomic DNA and encodes the protein hamartin [179, 222]. The majority (98% in TSC1 and 77% in TSC2) of mutations seen in both TSC1 and TSC2 are of a nature predicted to truncate the proteins, suggesting that these genes function as TSGs [reviewed in 222]. Further, LOH at both the TSC1 and TSC2 loci have been observed in TSC hamartomas, suggestive of Knudson’s ‘second-hit’. Of interest, intellectual disability has been more frequently associated with de novo mutation of TSC2 than TSC1 [223]. As is seen in the neurofibromatosis syndromes, mosaicism has been reported, having important implications for molecular diagnostics.
Hamartin has been shown to bind to proteins from the ERM family (see NF2 above), and loss of functional hamartin may lead to disruption of adhesion to the cell matrix, possibly via Rho-mediated signalling pathways [224]. Hamartin has been shown to physically interact with tuberin which is known to contain regions of homology to the rap1GAP and Rab5GAP GTPase activating proteins. Given this interaction, it is perhaps not surprising that loss of function of either hamartin or tuberin leads to loss of cell growth control regulation causing hamartomas to develop as part of the TSC phenotype [reviewed in 179, 222]. It is likely in the many tissues where hamartin and tuberin are co-expressed, that they may function together [225].
Renal Carcinoma Syndromes:
Renal malignancy occurs in a number of the familial cancer syndromes including the paediatric kidney cancer Wilms Tumour and VHL discussed elsewhere in this review, as well as HPRCC.
Hereditary Papillary Renal Cell Carcinoma (HPRCC)
Clinical Features
HPRCC (OMIM#605074) is a relatively recently recognised disorder, and unlike many of the other cancer syndromes whose malfunction of their genes target multiple tissues, this syndrome is site specific with HPRCC patients at-risk of developing bilateral, multifocal papillary renal cell carcinoma. HPRCC associated kidney tumours are distinct from VHL-associated clear cell renal tumours, and the papillary subtype accounts for approximately 10% of adult kidney tumours.
Molecular Determinants – MET
HPRCC is one of the few familial cancer syndromes whose germline mutation is in a proto-oncogene. Gain-of-function missense germline mutations have been identified in HPRCC patients in the catalytic domain of the MET proto-oncogene mapping to 7q31 and encoding a transmembrane receptor tyrosine kinase [226]. Further, trisomy of chromosome 7 has been observed in both sporadic and familial HPRCC tumours, and the mutated MET allele was duplicated in tumour cells [227]. It has been postulated that the germline mutation in MET does not disrupt normal development and that 2 copies of mutant MET are required to give the cells a proliferative advantage [227]. This may help to explain the relatively low penetrance of germline MET mutations in HPRCC. Functional studies of different point mutations in MET would suggest that different mutations may activate different pathways to direct the cell towards malignant transformation, that is either by inducing proliferation of the cells or protecting the cells from apoptosis [228]. Binding to MET by its ligand hepatocyte growth factor (HGF) induces MET dimerisation and autophosphorylation of the MET receptor, inititiating a signalling cascade via activation of the SOS/ras/extracellular kinase dependent (ERK) signalling pathway [229].
Paediatric Syndromes:
Whilst the majority of familial cancer syndromes affect adults, a small number affect very young children, likely due to mutation of genes critical for normal embryonic development. Two of these syndrome – Retinoblastoma and Wilms Tumour are discussed.
Retinoblastoma (RB)
Clinical Features
Retinoblastoma (RB; OMIM#180200), a paediatric tumour of the retinal cells, has served as a prototypic model for the study of susceptibility loci in familial cancer. The worldwide incidence of retinoblastoma has been reported at between 1 in 13 500 to 1 in 25 000, with the majority of patients being diagnosed before 3 years of age. Thirty-five to 45% of retinoblastoma are thought to be hereditary, of which 25-30% are bilateral and 10-15% are unilateral presentations [230]. However, the majority of germline cases are believed to be due to de novo mutation rather than familial transmission. Cases of bilateral disease are usually diagnosed earlier at an average age of 12 months, and patients with unilateral disease at an average age of 18 months. Presentations after 7 years of age are rare. Outcome for tumours contained within the eye are good, with cure rates up to 95%, however if the tumour has extended outside of the eye, mortality is high. Overall penetrance of familial retinoblastoma has been estimated to be between 85-95%, although pedigrees with lower penetrance have been described [reviewed in 231]. A higher incidence of second-site primary tumours including osteogenic sarcoma, malignant melanoma and benign and malignant tumours of the brain and meninges has been reported.
Molecular Determinants – RB1
RB1 was the first gene to be linked to a familial cancer syndrome, being definitively mapped in 1988 by positional cloning strategies to 13q14 and mutations identified [232]. Genetic heterogeneity is not seen in hereditary retinoblastoma, however deviations from the expected sex ratio for a non-imprinted gene have been observed [231]. The concept of a TSG was validated by early studies of pRB showing that re-introduction of wild-type pRB into cells lacking pRB resulted in suppression of anchorage-independent cell growth and had the ability to cause tumours in nude mice [233].
RB1 has 27 exons spanning 180 kb of genomic DNA, with mutations identified in most exons. The spectrum of mutations that occur include nonsense point mutations, with recurrent mutations at CpG dinucleotides that are part of CGA codons; missense point mutations occurring most frequently in amino acids encoding the pocket domains critical for protein binding; deletions and insertions; splices site mutations; intragenic rearrangements; mutations in the promoter and deletions at 13q14 [reviewed in 234]. Carriers of nonsense or frameshift mutations predicted to encode a truncated pRB usually develop the more severe phenotype of bilateral retinoblastoma.
Low penetrance retinoblastoma exists in some families, resulting in relatively late developing, often unilateral tumours and unaffected carriers. Mutations associated with this variant retinoblastoma phenotype are generally located in specific regions of RB1 [reviewed in 235]. A number of such families have been shown to harbour germline mutations in the RB1 promoter [236], missense mutations in the coding region [237], or mutations affecting splicing of RB1 [238]. It is likely that these mutations compromise, rather than abolish, the efficiency of pRB, resulting in decreased or de-regulated levels of pRB.
pRB, is a 110 kD nuclear phosphoprotein with a fundamental role in controlling the cell cycle, differentiation and apoptosis. pRB regulates the G1 phase of the cell cycle and cells lacking control at this point as a result of losing functional pRB show abnormal proliferation. Unphosphorylated pRB can bind E2F, leading to repression of E2F mediated transcription. However, during the G1 phase of the cell cycle, pRB is phosphorylated by CDKs and in this state, releases E2F that acts as a transcription factor to promote the expression of genes required for S phase entry and DNA synthesis. pRB has also been shown to associate with histone deacetylases providing evidence for pRB repressing transcription via histone deacetylation [reviewed in 239].
Thus, pRB is one of the most critical of all the gatekeepers and controls the transition from G1 to S phase of the cell cycle [reviewed in 235]. Recent studies have also implicated pRB as important in maintaining genomic stability [reviewed in 239].
Wilms Tumour (WT)
Clinical Features
WT (OMIM#194070), or nephroblastoma, is a paediatric malignancy of the kidney developing from the failure of embryonal mesenchymal blastema cells to differentiate into metanephric structures in the embryonic kidney, leading to their continued proliferation and the development of malignancy. It is relatively common, affecting one in 10 000 children, mostly occurring in children less than 5 years of age [240]. WT occurs sporadically in the majority of cases, but can also be due to a constitutive mutation. Up to 10% of presentations are bilateral, suggesting an underlying genetic predisposition. Between 1 – 2 % of bilateral cases are believed to occur as the result of familial transmission, the remainder occurring due to a de novo mutation. The small number of cases of familial transmission are perhaps surprising when one considers the relatively high survival rate, approximately 80% with the advent of modern chemotherapy, after treatment for WT, however reduced fertility, especially in the presence of developmental defects of the genitourinary tract, may be the true cause of this phenomenon [241]. Improved cure rates may be reflected in the future in an increased number of familial transmissions of this syndrome.
WT is often found in association with other congenital abnormalities and as part of syndromes including the WAGR (Wilms tumour, Aniridia (a malformation of the iris and surrounding tissue), Genitourinary abnormalities, mental Retardation) where >30% of cases develop WT, the Denys-Drash (characterised by the presence of WT, renal nephropathy and ambiguous genitalia) where >90% of cases develop WT and the Beckwith Wiedemann Syndrome (a congenital overgrowth syndrome defined by growth abnormalities and predisposition to a number of embryonal neoplasms including WT in <5% of cases) [242]. Other developmental type defects are also associated with WT including the presence of persistent nephrogenic rests that are primitive cells, providing strong evidence of a constitutional developmental defect of the kidney. WT has also been reported in a number of other familial syndromes with known susceptibility genes reviewed in this paper including NF1, breast-ovarian cancer syndrome, LFS, Bloom Syndrome (BS) and a further hereditary syndrome awaiting identification of its predisposition locus HPT-JT [243]. Anaplastic WT are an uncommon subtype associated with poor prognosis.
Molecular Determinants – WT1
WT displays genetic heterogeneity, with a number of loci having been linked to the development of WT in families including FWT1 at chromosome 17q12-q21 [244]; FWT2 at chromosome 19q13.3-13.4 [245]; and 11p15.5 where the imprinted gene IGF2 resides [246]. Still other families are not linked to these loci, suggesting that additional loci conveying susceptibility to hereditary WT exist [247]. To date however, only one gene, WT1 mapping at 11p13 and expressed primarily in foetal kidney, but also in the gonads, spleen and lining of the abdominal cavity has been identified as a susceptibility locus for WT [248-250].
In WTs of stromal-predominant histology and mutation of WT1, corresponding loss of the wild-type allele has been observed, or alternatively, point mutation of a second allele, suggesting that in a subset of WTs defined by histopathology, functional abrogation of a second allele conforming to Knudson’s ‘2-hit’ model is the primary cause of tumour development [251]. It has been suggested that the somatic ‘hit’ in WTs may occur early in the tumourigenic pathway given that identical WT1 mutations have been found in both tumour and the nephrogenic rests, suggesting that these distinct lesions share a clonal origin. While nephrogenic rests are poorly differentiated, they are not neoplastic, suggesting that additional genetic events are required to lead to WT [252].
WT1 consists of 10 exons encoding a protein with a proline / glutamine rich domain at the amino terminus, typical of transcription factors, and with 4 Cys2m-His2 zinc finger domains towards the carboxyl terminus [248, 253]. Four discrete transcripts are present due to alternative splicing at 2 sites [253]. Genotype-phenotype correlations have been attempted on a very small scale in cases of WT. Patients with the WAGR syndrome would appear to have mutations in WT1, including whole gene deletion, predicted to inactivate WT1 [251, 254]. The majority of patients with Denys-Drash syndrome appear to have predominantly missense mutations in zinc finger encoding exons of WT1 (92% of mutations) predicted to act in a dominant-negative manner by disruption of the zinc finger function of WT1 [255][reviewed in 256]. These mutations affect either amino acids directly involved in DNA binding or alternatively, the cysteine and histidine residues critical for zinc finger structure [256]. Further, families linked to the FWT1 locus would appear to present at a later stage and older age compared to those associated with mutations in WT1 [244]. Whilst studies such as this do point to clear genetic heterogeneity in WT, confirmation of these observations await both larger analyses and identification of the gene at FWT1.
WT1 functions as a zinc-finger transcription factor to repress transcription of a number of growth promoting genes via DNA binding. WT1 mutants have been shown to decrease both the transcription repressing activity and growth-inhibitory function of wild-type WT1 [257]. In its role as a transcriptional repressor, WT1 has been shown to repress transcription from the promoter region of a number of genes including insulin-like growth factor II, early growth response gene, c-Myc and n-Myc [reviewed in 258]. A number of these genes, including n-Myc are co-expressed in the embryonal kidney along with WT1 and are overexpressed in a subset of WTs. It has been postulated that WT1 functions to regulate the expression of certain oncogenes, such as n-Myc, that normally are active only at certain stages of embryogenesis.
AUTOSOMAL RECESSIVE FAMILIAL DISORDERS
A number of autosomal dominantly inherited syndromes characterised by chromosomal instability and defects in DNA repair leading to increased risks of developing malignancies have been identified and include Werner Syndrome (WS), Xeroderma Pigmentosum (XP), Rothmund-Thomson Syndrome (RTS), Bloom Syndrome (BS), Ataxia-Telangiectasia (A-T) and Fanconi Anaemai (FA). There is some evidence that A-T and XP heterozygotes may also have an elevated risk of developing malignancies. Given a role for many of the genes associated with these syndromes in DNA repair, they would seem to function as caretakers of the genome.
Werner Syndrome (WS)
WS (OMIM#277700) is characterised by genetic instability and premature age of onset related diseases. Patients with this condition develop artherosclerotic-related disease, cataracts, osteoporosis and adult onset diabetes mellitus. Cultured fibroblast and lymphocyte cells from WS patients exhibit a limited capacity to proliferate [259]. Further, these cells exhibit cytogenetic and/or molecular genetic instability, developing various aberrations including translocations, inversions and extensive deletions [260, 261]. The WS gene WRN maps to 8p12 and encodes a DNA helicase, which is homologous to Escherichia coli RecQ, belonging to the RecQ helicase family. WRN also has 3’-5’ exonuclease activity. There are 4 other RecQ helicases known, 2 of which are associated with other chromosomal instability syndromes – BLM in BS (OMIM#210900) and RECQL4 in RTS (OMIM#268400). There are however some clear phenotypic differences between these syndromes. BS, for example, manifests mainly in children with blood cancers, while WR manifests in young adults with premature aging and an increased risk of developing soft tissue sarcomas. The genetic instability associated with BS is represented by increased rates of sister chromatid exchanges while the instability in RTS consists of increased chromosomal rearrangements [262]. All of these genes therefore appear to play a role in maintaining the integrity of genetic information. WRN mutations encode truncated proteins consistent with a loss of function leading to WS. This is in contrast to BS where missense mutations are reported in BLM in addition to mutations predicted to truncate the protein [263]. The helicase and exonuclease activities of WRN may function together on alternate DNA structures. WRN likely has multiple roles and several theories have recently been reviewed [264, 265]. It may be that the exonuclease activity of WRN excises altered nucleotides during DNA synthesis and functions as a DNA processing or editing enzyme assisting cells to correct DNA structures which have been altered during DNA metabolic processes or DNA damage [264, 265].
Xeroderma Pigmentosum (XP)
XP is characterised by extreme sensitivity to sunlight with skin cancer development at a very early age. Freckles in exposed areas occur in the first years. One large study of 132 patients with XP found malignant skin neoplasms in 70% of patients with a median age of 8 years, basal cell or squamous cell carcinoma in 57%, and melanoma in 22% [266]. The frequency of melanomas, like the frequency of non-melanoma skin cancers, anterior eye cancers, and tongue cancers, was also increased. It has also been suggested that heterozygosity for XP genes may predispose carriers to skin cancer, particularly in association with substantial exposure to sunlight, which might overwhelm the normal function of DNA repair enzymes [266, 267].
Normal skin fibroblasts repair ultraviolet radiation damage to DNA by inserting new bases into DNA while XP cells have a deficiency in nucleotide-excision repair preventing the repair of thymine dimers formed after ultraviolet light exposure [268]. Seven complementation groups (A-G) have been identified in the class of XP patients with defective excision of pyrimidine dimers (excision-deficient XP). In addition, one form appears to have a defect in post-replicative repair. Several genes have now been implicated in XP [269]. The letter designation used in naming this condition is given in reference to the cell line in which the mutation was identified. In XPA (OMIM#278700) the protein is mutated and patients with this condition have a high risk of developing solid tumours and skin cancers as well as premature aging. XPA and XPC (OMIM#278720) have a high relative frequency of deficiency in nucleotide excision repair; XPD (OMIM#278730) and XPF (OMIM#278760) have an intermediate frequency; and the remaining complementation groups are rare [270].
Rothmund-Thomson Syndrome (RTS)
RTS is caused, at least in some affected families, by mutation of the DNA helicase gene RECQL4 located at 8q24.3. Characteristically, patients with RTS have skin atrophy, telangiectases, juvenile bilateral cataracts, saddle nose, congenital bone defects, disturbances of hair growth, hypogonadism and are at-risk of developing osteosarcoma [271]. Trisomy 8 mosaicism has been described [272] as well as lymphocyte chromosomal abnormalities [273]. It has been suggested that RTS may be associated with clonal rearrangements causing acquired somatic mosaicism [274]. Since the genes responsible for WS and BS were found to be homologues of Escherichia coli RecQ, which encodes a DNA helicase that unwinds double-stranded DNA into single-stranded DNA, an analysis of other eurkaryotic homologues revealed compound heterozygous mutations in RECQL4, which encodes a member of the RecQ helicase family, in some but not all patients with RTS [275, 276].
Bloom Syndrome (BS)
BS is another of the chromosome instability conditions, the gene for which, BLM, also encodes a DNA helicase RecQ protein and maps to 15q26.1. BS is characterised by short stature and skin manifestations in the form of exaggerated sun-sensitive telangiectatic lesions, pigmentation changes and a large predisposition to malignancy, likely of all cell types and sites [277, 278]. A founder mutation in BLM in the Ashkenazim, 2281 delta6ins7, has been identified, with a carrier frequency of approaching 1% [279]. Multiple chromatid and chromosome breaks as well as chromatid exchanges are common. The non-specific chromosomal breaks observed in BS are similar to those seen in FA, however in BS, most interchanges are between homologous chromosomes, ie. sister chromatid exchanges, whereas in FA, interchanges are usually between non-homologous chromosomes. The presence of these sister chromatid exchanges can be used in assisting with the diagnosis of BS [280]. BLM is a member of the RecQ gene family, named after Escherichia coli RecQ. Escherichia coli RecQ is a member of the RecF recombination pathway, a pathway that regulates conjugational recombination proficiency of DNA and resistance to ultraviolet radiation in cells [281]. It is therefore presumed that BLM encodes a protein involved in DNA recombination. Although it is still unclear how disruption of BLM leads to the chromosome instability seen in BS, BLM appears to be involved in the surveillance of nucleotide abnormalities in genomic DNA that may be encountered by replication forks in early S phase [282]. Such surveillance would assist in maintaining genomic stability. The increased chromosomal breakage seen in BS may predispose to tumourigeneisis by oncogene activation through mutations or translocations and loss of function of TSGs by chromosomal deletions in a similar fashion to that seen in FA.
Ataxia-Telangiectasia (A-T)
A single gene, ATM, located at 11q22-23 has been implicated in A-T (OMIM#208900), encoding a product similar to the p110 subunit of PI-3 kinase [283] and playing an important role in several DNA damage recognition systems. The clinical findings in A-T include progressive neurological disease in the form of cerebella ataxia and oculomotor apraxia, oculocutaneous telangiectasia, elevated serum alpha-fetoprotein, immunodeficiency, hypersensitivity to ionising radiation, premature aging and cancer susceptibility, predominantly leukaemia or lymphoma. About 40% of A-T homozygotes develop a malignancy [284]. The Acute Lymphocytic Leukaemia (ALL) seen in children is usually of T-cell origin but the more common pre-B cell leukaemia has also been described [285]. In adults, leukaemia presents as T-cell leukaemia that looks similar to Chronic Lymphoblastic Leukaemia (CLL) [286]. The blood cancer cells are often found with an aberration involving the T cell receptor alpha chain gene complex at 14q11-12. Lymphomas in these patients however are often of B-cell type although T-cell lymphomas are occasionally seen. Older patients are prone to develop breast cancer, melanoma and Hodgkins Disease with other tumour types also occasionally found. ATM is multifunctional and has a role in maintaining genomic stability, appearing to control multiple cellular stress responses [287].
The instability seen in A-T is limited to T cells. Chromatid breaks, chomatid exchanges and telomeric associations are not as prominent as in FA and the rearrangements in contrast to FA are specific as for example inv(7), and usually involving 7p14, 7q35, 14q11-12 and 14q32. It appears that the breakpoints all involve an immunoglobulin family gene and that the rearrangements occur secondarily to recombination between these genes. The malignant predisposition of A-T is thought to be determined through multiple ATM functions and DNA hypomethylation might also be a contributing factor [288]. Further, it has been suggested that ATM heterozygotes with specific non-truncating mutations may carry an increased risk of breast cancer [289, 290], although studies have also suggested that heterozygous ATM mutations do not confer an increased risk for the development of early onset breast cancer [291].
Fanconi Anaemia (FA)
FA is usually first brought to the attention of physicians due to short stature and a variety of congenital anomalies including skeletal defects especially radial and thumb defects, gastrointestinal anomalies and central nervous system abnormalities. Haematological findings are common, especially bone marrow failure and Acute Myeloid Leukaemia (AML). These malignancies often appear with losses or deletions of chromosomes 7 and 5 and unbalanced rearrangements are commonly seen, different to those seen typically in AML independent of FA [292]. Besides the increased risk of blood cancers, there is also an increased risk of other malignancies, especially gastrointestinal and gynaecological cancers [293]. There are at least eight complementation groups in FA: A, B, C, D1, D2, E, F and G [294], with a number of susceptibility loci having been cloned. Complementation Group A is responsible for most of the cases of FA and together with complementation groups C and G accounts for the vast majority of cases. A large number of mutations exist within each complementation group and a mutation database has been created ( http://www.rockefeller.edu/fanconi/mutate/).
There is poor genotype-phenotype correlation between the complementation groups but genotype-phenotype correlations exist for specific mutations [295]. Chromatid breaks, exchanges and deletions are common, as well as partial endoreduplication, a type of duplication seen in all complementation groups. These changes appear to be related to DNA replication and are especially sensitive to cross-linking agents [296]. The DNA repair /replication defect may result in gene silencing through accumulated deletions in TSGs. Mutations within TSGs may be unmasked by larger deletions or further mutations in the wild-type allele. Chromosomal instability caused by mutations may also allow formation of stable unbalanced rearrangements that may participate in tumourigenesis. Abnormal cell replication may also explain the observed frequency of chromosomal instability in FA.
MODIFIERS OF GENE EXPRESSION WITHIN CANCER SYNDROMES
Many of the disorders discussed in this review, despite their apparent clarification at the molecular level, have a vast range of penetrance and expressivity, both within members of the same family carrying identical mutations and between affected families carrying the same or different mutations. A number of reasons have been suggested to explain this phenomenon including genotype-phenotype correlations, the accumulation of genetic or epigenetic second ‘hits’ required for tumour progression, parent-of-origin effects (imprinting), the role of the environment and the presence of modifier loci. Additional evidence for the presence of modifier loci is found in mouse models of disease where mice with certain genetic backgrounds often express the same genetic disease very differently. A modifier locus, Mom-1 (Modifier of Min-1), has been identified in the Min mouse (a mouse model for FAP carrying a mutant mouse Apc that develops intestinal adenomas) and may have relevance in human disease [297, 298].
A number of examples of genotype-phenotype correlations have been summarised within this review including the correlation of the RET mutation M918T with MEN 2B [20], and the position of mutations within APC and disease severity [5]. It is also possible that missense mutations at known disease gene loci may serve to act as low to moderately penetrant loci, increasing the risk of developing cancer. One of these such mutations is the I1307K APC mutant found in approximately 6% of the Ashkenazim that is thought to cause a 2-fold increased risk of developing CRC in this population by creating a mutational ‘hot-spot’ [103]. It has been suggested that the accumulation of several rare variants such as this may contribute significantly to the risk of developing cancer [299]. It is possible that silent, or perhaps even non-coding mutations, may generate substantial interest in the future as potential modifiers of disease expression.
It has long been accepted that the environment has a role in modifying the penetrance and expression of inherited disease genes. For example, the expression of germline mutations in FMM is markedly influenced by environmental exposure to ultraviolet radiation. Further, correlations have been drawn between PGLs and normal carotid bodies, an organ involved in oxygen sensing, when challenged by chronic hypoxic stimulation at high altitudes. It is intriguing to speculate that the development of familial PGL, primarily caused by mutations in the genes encoding subunits of the mitochondrial complex II, may be modified by environmental oxygen levels [300]. In addition, gene expression in a subset of familial PGL, those caused by SDHD mutation, is modified by parent-of-origin effects, manifesting as an absence of maternal disease transmission.
SUMMARY
Elucidation of the primary genetic basis of a number of the familial cancers has meant that a molecular diagnosis is now possible for many of these syndromes, allowing directed cancer surveillance for members of families determined to be at-risk of developing disease. Due to the large size of a number of these genes such as BRCA1, BRCA2, NF1 and NF2, and the lack of mutation ‘hot-spots’, efficient mutation screening is still a challenge in many cases. However, for small genes such as VHL, or genes such as RET where mutations are localised at specific codons, genetic testing has largely been incorporated into the clinical management of affected families. Genes for a number of syndromes including non-medullary thyroid carcinoma, familial prostate cancer and HPT-JT await identification. Increasing knowledge of both the role of cancer predispositon genes in normal development, adult tissue and malignancy, and the additional ‘hits’ that occur in many cases to promote tumourigenesis, will revolutionise the treatment of cancer by allowing therapeutic intervention at the molecular level.
Acknowledgements
The authors would like to acknowledge work in the field not cited due to space restrictions. D. Benn is thanked for helpful discussions. DJM is a R. D. Wright Fellow (NHMRC, Australia).
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Figure 1. Time line of discovery of genes mutated in the germline of patients with autosomal dominantly inherited familial cancer syndromes.
Figure 2. Ideogram outlining the chromosomal location of genes implicated in the autosomal dominantly inherited familial cancer syndromes.
Table I: Genes associated with the autosomal dominant hereditary cancer syndromes
| SYNDROME | GENE | PREDOMINANT TUMOURS | LOCATION | FUNCTION / CLASSIFICATION |
| Breast/ovarian | BRCA1 BRCA2 | breast carcinoma, ovarian carcinoma female and male breast carcinoma, prostate cancer | 17q21 13q12.3 | DNA repair DNA repair |
| Carney Complex | PRKAR1A | pituitary adenoma, testicular neoplasms, thyroid adenoma and carcinoma, breast ductal adenoma | 17q22-q24 | role in the cAMP pathway |
| Cowden Syndrome | PTEN/MMAC1/TEP1 | breast carcinoma, thyroid (follicular adenoma, follicular carcinoma and papillary carcinoma), endometrial carcinoma | 10q23.3 | protein tyrosine phosphatase |
| FAP |
APC |
adenomatous polyps of the colorectum, increased gastrointerstinal cancer risk, papillary thyroid carcinoma | 5q21 | regulation of cell proliferation, migration and adhesion, cytoskeletal reorganisation, chromosomal stability |
| Familial melanoma |
CDKN2A
CDK4 |
cutaneous malignant melanoma, pancreatic cancer cutaneous malignant melanoma | 9p21 12q14 | cell cycle regulation at the G1/S checkpoint |
| Hereditary Papillary Renal Cell Carcinoma | MET | papillary renal cell carcinoma | 7q31 | transmembrane receptor tyrosine kinase |
| Hereditary paraganglioma and phaeochromocytoma | SDHD SDHC SDHB | paraganglioma, phaeochromocytoma | 11q23 1q21 1p36.1-p35 | possible involvement in the regulation of oxygen sensing and signalling |
| HNPCC | hMSH2 hMSH6 hMLH1 hPMS1 hPMS2 | colorectal and endometrial adenocarcinoma | 2p22-21 2p16 3p21 2q31-33 7p22 | DNA mismatch repair |
| Juvenile Polyposis Coli | SMAD4/DPC4 BMPR1A | multiple juvenile polyps in the gastrointestinal tract, colorectal and gastrointestinal malignancy | 18q21.1 10q21-q22 | cytoplasmic mediator in the TGF-β signaling pathway serine-threonine kinase type 1 receptor |
| Li-Fraumeni | TP53 hCHK2 | breast cancer, soft tissue sarcoma, brain tumours, adrenocortical tumours, leukemia | 17p13 22q12.1 | transcription factor, cell cycle regulation, apoptosis checkpoint kinase, DNA damage response |
| MEN 1 | MEN1 | primary hyperparathyroidism, pancreatics islet cell tumours, anterior pituitary tumours | 11q13 | mediator of JunD transcriptional activity; possible role in TGF-β signaling via Smad3; unknown |
| MEN 2 |
RET |
medullary thyroid carcinoma, phaeochromocytoma, mucosal neuromas (MEN 2B only) | 10q11.2 | transmembrane receptor tyrosine kinase |
| Nevoid BCC | PTC | basal cell carcinoma | 9q22.3 | development, negative regulator of cell division |
| NF1 |
NF1 |
neurofibrosarcoma, astrocytomas, phaeos, melanoma, rhabdomyosarcoma and chronic myeloid leukemias | 17q11 | negative regulator of RAS-mediated cellular proliferation; |
| NF2 | NF2 | bilateral vestibular schwannomas, meningiomas, spinal tumours, skin tumours | 22q12 | maintenance of the cytoskeleton, suppressor of cell adhesion, motility and spreading |
| Peutz-Jeghers | STK11/LKB1 | gastrointestinal tract carcinoma, breast carcinoma, testicular cancer, gynaecological malignancies | 19p13.3 | serine threonine kinase |
| Retinoblastoma |
RB |
paediatric retinal tumours | 13q14 | cell cycle regulation, apoptosis |
| Tuberous sclerosis |
TSC1
TSC2 |
multiple hamartomas, renal cell carcinoma, astrocytoma | 9q34 16p13 | maintenance of the cytoskeleton |
| VHL |
VHL |
renal cell carcinoma, retinal and central nervous system haemangioblastomas, phaeochromocytoma | 3p25 | promotes fibronectin matrix assembly; component of a ubiquitin ligase complex targeting HIF-1 for degradation |
| Wilms tumour |
WT |
paediatric kidney tumours | 11p13 | transcriptional regulation |
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