Key words: glioblastoma, amplification, tumour suppressor gene, EGFR., p53, RB1, brain tumor, LOH, chromosome

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

The astrocytomas are the commonest form of gliomas and primary tumours of the brain in man. These tumours are classified and malignancy graded according to empirically derived histological criteria. The World Health Organisation (WHO) has recently published current criteria for classification and malignancy grading [1]. The WHO malignancy grading has been shown to correlate to the biological behaviour of the individual types tumours, and ranges from malignancy grade I (the least biologically aggressive) to grade IV, (the most malignant). Some tumour types have only one grade others up to four. The terminology used in this paper will correspond to the most recent WHO report [1].

Astrocytic tumours constitute 65-70 per cent of all gliomas and are malignancy graded on the basis of histological features into grades I-IV [1]. The pilocytic astrocytomas (malignancy grade I) are the least malignant, occur mainly in children, only very rarely progress to more malignant tumours and have generally a good prognosis. Consequently they will not be discussed further in this text. In contrast, the adult diffuse astrocytic tumours frequently show malignant progression. The adult diffuse astrocytomas include the Astrocytomas (malignancy grade II), the Anaplastic Astrocytomas (malignancy grade III) and the Glioblastomas (malignancy grade IV) and these will be the main focus of this text. The average survival of patients with an astrocytoma (malignancy grade II) is around 7 years [2], while patients with anaplastic astrocytomas have a median survival half that time [3]. Glioblastoma patients have a very poor prognosis with average survival reported between 9 and 11 months despite modern therapy [4]. Grade II tumours have a peak incidence between 25 and 50, while the glioblastomas have a peak incidence between 45 and 70 years. Glioblastomas are the most common form and are divided into those that develop from a previously diagnosed Astrocytoma or Anaplastic Astrocytoma (secondary Glioblastomas) and those that appear to develop de novo – that is with no evidence of there having been an earlier tumour of lesser malignancy grade [3]. There are clinical and molecular data to support the hypothesis that these tumours may develop in different ways [5-8].

ASTROCYTOMAS (MALIGNANCY GRADE II)

The cytogenetic and molecular data on astrocytomas is limited [9-11]. Over 60% of astrocytomas have losses of alleles on 17p including the TP53 locus and the retained TP53 allele is mutated in the majority of cases [8]. The absence of wild type p53 is therefore the commonest abnormal finding in astrocytomas malignancy grade II [8], resulting in a non-functional p53 pathway (see Fig.1). A small percentage have mutations of one allele but retain one wild type allele. As the p53 protein is believed to function as a tetramer and as tetramers with one abnormal protein component may not function normally, the finding of a single mutated allele may also be significant. The MDM2 and p14ARF genes have been studied in small numbers of these tumours and no abnormalities have been reported. Recent studies of the TP53 related gene, P73, have not identified any mutations[12]. Other findings considered significant include overexpression of the PDGFRA gene [13, 14].

Loss of alleles from 6q, 10p, 13q, and 22q occur in some astrocytomas. There is no evidence to suggest that there is mutation of the single retained tumour suppressor gene RB1 allele at 13q14.2 [15] or the NF2 tumour suppressor gene on 22q [16, 17]. Deletion mapping of chromosomes 6 and 10 shows losses on 6q and the distal end of 10p in a significant number of astrocytomas [18, 19]. The potential tumour suppressor genes in all of these regions remain unknown. There are no consistently reported amplified genes or regions of the gliomas in astrocytomas [15, 20-22]. The changes found in the astrocytomas form the baseline for progression in the adult diffuse astrocytic tumour series. Epigenetic changes such as hypermethylation of tumour suppressor gene promoters may also play an important role in transcriptional silencing of important cancer genes and the development of astrocytomas. This has not been studied in any detail as yet [23].

ANAPLASTIC ASTROCYTOMAS (MALIGNANCY GRADE III)

The numbers of cases of Anaplastic Astrocytomas studied is also limited. There are also some practical problems in studying a series of Anaplastic Astrocytomas. In sparsely sampled tumours the diagnosis can only indicate a minimum malignancy grade – there could be regions fulfilling the criteria for Glioblastoma elsewhere. Thus in a series of Anaplastic Astrocytomas there may be some Glioblastomas while there will be no Anaplastic Astrocytomas in a Glioblastoma series as once the criteria for Glioblastoma are fulfilled the tumour cannot be classified as anything other than a Glioblastoma. However, this applies only to a clinical diagnosis that is always based on the worst findings in a tumour. Naturally in a tumour that is progressing from one malignancy grade to another there will remain tumour cell populations of the lesser malignancy grade that might be included in a sample for molecular analysis. Thus the findings have to be interpreted with care and relatively large series are necessary to enable a correct interpretation of the findings. Cytogenetics, comparative genomic hybridisation and molecular genetic techniques all show that the losses of alleles on 6q, 10p, 13q, 17p and 22q, as seen in the astrocytoma malignancy grade II and they occur at similar or higher frequencies in the anaplastic astrocytomas. Mutations of the TP53 gene also occur at approximately the same frequency [8]. Thus in the anaplastic astrocytomas the p53 pathway is also non-functional and in the majority of cases (approximately 67%) and this is due to mutations of the TP53 gene. With the sole exception of losses of alleles on 19q (targeted gene(s) unknown) there are no conclusively demonstrated abnormalities specific to this malignancy grade. Around 20% of anaplastic astrocytomas show similar genetic abnormalities to those found in glioblastomas and discussed below [8, 15, 24].

GLIOBLASTOMAS (MALIGNANCY GRADE IV)
The histological criteria for Glioblastomas are well defined and these tumours if adequately sampled, are generally easy to differentiate from the astrocytomas of lower malignancy grade. Despite this, Glioblastomas developing from tumours of lesser malignancy grade (secondary Glioblastomas) may retain in the primary tumour populations of cells that represent the different stages that the tumour went through during its progression. Secondary glioblastomas have only been studied in relatively small numbers for a myriad of reasons [25]. However, the high frequency de novo glioblastomas has permitted their study in considerable numbers. Glioblastomas show the greatest numbers of genetic abnormalities among the astrocytic tumours and clear patterns of abnormality in these tumours are emerging. In addition to the targeting of the p53 pathway as is seen in the astrocytomas and anaplastic astrocytomas the mechanisms controlling cellular entry into the S-phase of the cell cycle is also rendered inoperative (Fig.1).
In contrast to the astrocytomas and anaplastic astrocytomas, the glioblastomas abrogate the p53 pathway in different ways. Some have no wild type TP53 gene, as found in the astrocytomas of lower malignancy grade (approximately 37% [8]), but note that this incidence is much lower. Others have wild type TP53 genes but mutate genes coding for proteins that control cellular levels of p53. The mutations found lead to the rapid brake-down of the wild type protein resulting in a cell with little or no wild type p53. Levels of wild type p53 are controlled post-translationally by the activity of pMDM2. pMDM2 shuttles p53 from the nucleus to the cytoplasm where pMDM2 functions as an E3 ubiquitin ligase leading to the degradation of p53 [26, 27]. The MDM2 gene is amplified and overexpressed in some glioblastomas with wild type TP53 alleles. The function of pMDM2 is controlled in its turn by p14ARF in dividing cells. The p14ARF gene is homozygously deleted and the protein thus absent in some glioblastomas. Glioblastomas thus have either no wild type p53 or no p14ARF or overexpress pMDM2 as mutually exclusive genetic abnormalities [8]. While only approximately 37% of glioblastomas have mutations of the TP53 gene, around 75% can be shown to have abnormalities of the p53 pathway when only these 3 genes are examined (TP53, MDM2, p14ARF). Methylation of the promotor of the p14ARF gene with decreased or non-expression are further mechanisms that have been shown to be involved in some tumours. Other components of the p53 pathway are suspected of being aberrant in the remaining fifth of tumors.
In a similar manner one or other of the genes coding for proteins involved in the RB1 pathway controling entry into the S-phase of the cell cycle, are also mutated in glioblastomas (Fig.1). Entry into S-phase is normally initiated by the release of transcription factors from a newly phosphorylated pRb1 at the restriction point in G1. Unphosphorylated pRb1 normally sequesters the pE2F transcription factors [28]. Loss of the wild type RB1 gene resulting in no functional pRB1 or inappropriately phosphorylated pRb1 will result in any expressed pE2F being free to initiate transcription of the genes necessary for entry into S-phase. Non-expression of a wild type allele due to hypermethylation of the promotor region is another event that has been shown to occur in Glioblastomas [29]. Inappropriate phosphorylation may be achieved in glioblastomas that have wild type pRb1 by either loss of wild type p16 expression or over-expression of pCDK4 due to amplification of its gene. These would make inappropriate phosphorylation of a wild type pRB1 more likely with the release of the pE2Fs. p16 normally binds pCDK4 and thus inhibits the formation of the pCDK4/cyclin D1 heterodimer necessary for Rb1 phosphorylation [30]. In the absence of p16 all expressed pCDK4 is available for heterodimer formation. When pCDK4 is overexpressed in the presence of normal levels of p16 there will be excess pCDK4 available for heterodimer formation. One or the other of these abnormalities are present in over 90% of glioblastomas and are with very few exceptions mutually exclusive [8].
While disruption of the p53 and Rb1 pathways seem essential for glioblastomas, the ways in which the pathways are rendered dysfunctional may confer slightly different biological characteristics on the individual glioblastoma. There are further genetic abnormalities in glioblastomas. Over 90% lose alleles from 10q. The regions consistently lost include the variously named PTEN/MMAC1/TEP1 tumour suppressor gene at 10q23-24 [19, 31, 32]. PTEN has been shown to be mutated in over 45% of a large series of Glioblastomas [33]. The gene is a dual-specificity phosphatase (necessary for its ability to function as a tumour suppressor) and has homology to the cytoskeletal protein tensin [34, 35]. One of its major substrates is phosphatidylinositol-3, 4, 5,-trisphosphate (PIP3) [36] and lack of control of PIP3 half-life is likely to have a major affect on the Akt pathway, affecting among other things HIF-1 activity [37]. This is supported by recent reports on the affect of Akt activation in an animal model of astrocytoma [38].
The Epidermal Growth Factor Receptor (EGFR) gene (7p11-12) is amplified in about 35% of glioblastomas. When amplified this gene is always over-expressed but it is also over-expressed in many Glioblastomas the absence of amplification. Rearrangements of the amplified gene occur in almost half of the tumours with amplification. The most common rearrangement results in a transcript that is aberrantly spliced, yet remains in frame [39-41]. The aberrant transcript codes for a mutated pEGFR that has lost 267 amino acids of its extracellular domain and does not bind ligand [42, 43]. This mutated pEGFR is constitutively activated [42, 43] and attempts are ongoing to target therapy to this aberrant cell surface molecule [44, 45]. Other rearrangements of the amplified EGFR gene occur less frequently and may result in abnormalities of the cytoplasmic domain [46].
Glioblastomas can develop from an astrocytoma or as a de novo glioblastoma. It is tempting to try to sort all these findings into a series of events explaining the development of the two forms of glioblastoma. The de novo tumours may develop by a minimum number of genetic events when amplification of the 12q14 region encompassing the CDK4 and MDM2 genes resulting in their overexpression and the disruption of the normal p53 and Rb1 pathways. Another way would by the homozygous deletion of the region on 9p encompassing the genes coding for p16 (CDKN2A), p15 (CDKN2B) and p14ARF (p14AR)). The latter requires losses from the two autosomes but also leads to the abrogation of both the Rb1 and the p53 pathways. Clinically de novo tumours may also may also show more complex patterns of mutations with loss of one allele of each of TP53 and RB1, with mutation of the retained alleles, however these are in the minority. Tumours that progress from astrocytomas to glioblastomas generally have no wild type p53 and accumulate other changes such as loss of wild type RB1. Other correlations are that EGFR amplification is unusual in cases with no wild type p53 although this does occur occasionally. In addition to the abnormalities of the genes listed there are likely to be many other genetic changes affecting other regions of the genome that have been found to be manifestly abnormal in these tumours by deletion or amplicon mapping. The genes targeted by these changes have yet to be identified.

IMPACT OF MOLECULAR FINDINGS ON CLINICAL MANAGEMENT AND THERAPY
The use of molecular findings in providing usefull prognostic information in astrocytic tumours has yet to be realised. There have been many studies providing results that are frequently difficult to interpret [47-49]. The age of the patient at diagnosis and the histopathological information still provide the most useful data. We should not be disheartened by this as our understanding of the workings of the normal and malignant cell are as yet rudimentary. Many of the molecular and genetic findings outlined above have also resulted in attempts to experimentally design therapies to block or reinstate the cellular mechanisms activated or deranged by the mutations observed [50]. Some have even got to the stage of phase I and II trials. While many have built on careful observation of human tumour tissue and extensive experimental manipulation in laboratory tests no clear therapeutic brake-through has yet occurred. However we can expect that the more we understand the complex mechanisms of the normal cell as well as the aberrations that occur in the malignant cell we will be able to find ways of specifically treating malignant disease, leaving the normal surrounding brain less, if not entirely, undamaged.

Acknowledgements
The author thanks the many researchers in the field of molecular Neurooncology who have contributed to the data summarised in this paper and apologises for not directly citing their work due to space constraints. Our own work was supported by grants from the Swedish Cancer Society, Ludwig Institute for Cancer Research and Cancer Research UK.

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