Abstract
The Wnt signaling pathway has long been known to direct growth and patterning during embryonic development. Recent evidence also implicates this pathway in the development of childhood tumors of the liver, the kidney, the brain, and the pancreas. Here we review the current evidence on how constitutive activation of the Wnt signaling pathway may occur in hepato-, nephro-, medullo- and pancreatoblastomas. With particular emphasis the mutational activation of CTNNB1, an emerging major oncogene in solid childhood tumors, is discussed.

Keywords: Wnt signaling pathway; Hepatoblastoma; Wilms tumor; Nephroblastoma; Primitive neuroectodermal tumor; PNET; Medulloblastoma; Pancreatoblastoma; ß-Catenin; APC; Mutations

Abbreviations: BWS, Beckwith-Wiedemann-Syndrome; DMH, 1,2,-dimethylhydrazine; EGL, external granular layer; FAP, familial adenomatous polyposis; HB, hepatoblastoma; MB, medulloblastoma; NB, nephroblastoma; PB, pancreatoblastoma; PNET, primitive neuroectodermal tumor; WS, Wnt signaling

1. Introduction

Childhood cancer in many aspects is distinct from cancer in adults. Malignant tumors in children are rare and they typically arise from germinal tissues, as opposed to the epithelial origin of most cancers in adults. Childhood tumors have a relatively fast growth rate and upon diagnosis they frequently present as large tumor masses and with considerable potential for metastatic spread. Local therapy alone is rarely successful and nearly all children with tumors require systemic therapy to be cured. Fortunately enough, pediatric tumors display a high sensitivity to chemotherapy and radiation.

Important information about the molecular pathogenesis of childhood cancer has been derived from the study of normal embryonic development. The similarities between the growth and differentiation of cells and tissues and the dysregulation of these events in oncogenesis are evident at multiple phenotypic levels. Massive cell proliferation, migration into neighbouring compartments, and cellular differentiation are features common to both normal embryonic and cancer development. At the molecular level, this relationship has become substantial with the discovery that many proto-oncogenes encode components of signal transduction pathways which direct normal development. One such pathway, the Wnt signaling pathway, plays a well-established role during normal embryonic development. More recently, the Wnt signal transduction pathway has been implicated in the development of different solid childhood tumors, among them hepatoblastomas, nephroblastomas, medulloblastomas, and pancreatoblastomas.

It is the aim of this review to summarize these findings and to discuss their potential implications for the current view on how these tumors arise. To achieve this, we will first describe the functionality of the Wnt signaling pathway. Thereafter the four solid childhood tumors, hepatoblastoma, nephroblastoma, medulloblastoma, and pancreatoblastoma, with known genetic lesions in genes encoding Wnt signaling members, will be compared concerning their molecular genetics, their respective embryonic stem cell of origin and their particular histopathological appearence.

2. The Wnt signal transduction pathway
Wnt signaling (WS) is involved in different developmental processes such as cellular proliferation, differentiation, and epithelial-mesenchymal interactions and it does so in a wide range of tissues. At the very earliest stages of embryogenesis it is a Wnt-signal that controls formation of the main body axis [1], later on, WS is required for development of many organs, including the brain [1;2] kidney [3;4], mammary gland [5-8], reproductive tract [9;10], vasculature [11], thymus [12], hair follicle [13], and teeth [14-16]. Recent evidence further implicates WS in adult tissue homeostasis and the maintenance of stem cell compartments in fast-renewing epithelia like the small intestine [17].

WS is initiated upon binding of a secreted Wnt-molecule to its cognate receptor frizzled (frz), a seven-pass transmembrane protein (figure 1). The vast number of different cellular responses elicited by WS can be at least partly understood by the complexity of the Wnt- and frz-gene families themselves: in humans, for instance, at least 19 Wnts and 10 frz receptors have been identified. Depending on the particular Wnt/frz combination active, intracellular signaling downstream of the receptor may then branch into three major effector pathways: the Wnt/Ca²⁺ pathway, which regulates cell adhesion and motility through activation of phospholipase C, protein kinase C and Ca²⁺-Calmodulin-dependent kinase II [18], the planar cell polarity (PCP) pathway, which regulates cell polarity and morphogenetic movements via activation of c-jun aminoterminal kinase (JNK) [19], and the canonical Wnt/ß-catenin pathway which regulates cell differentiation and proliferation through ß-catenin/TCF-mediated transcriptional activation of Wnt-target genes [20]. It is the latter pathway, the Wnt/ß-catenin pathway, which has been strongly implicated in human cancer and which will be briefly summarized here.

Fig. 1. The Wnt signaling pathway in cancer and normal development. A Wnt-signal is elicited by binding of a secreted Wnt-molecule to its cognate receptor. This leads intracellularly via the dishevelled (DSH) protein to inactivation of the ß-catenin destruction complex and stabilization of the ß-catenin protein. ß-Catenin then enters the nucleus, associates with TCF/Lef transcription factors and stimulates the transcription of crucial target genes. Mutation of APC or ß-catenin itself may lead to uncoupled intracellular signalling.

In the absence of Wnt-molecules an intracellular multi-protein complex containing casein kinase 1 (CK1-) alpha, glycogen-synthetase kinase (GSK)-3ß, the adenomatous polyposis coli (APC) protein, axin and conductin (AXIN2 in human), constantly phosphorylates another protein, ß-catenin. Phosphorylation occurs in a sequential manner. The triggering event is phosphorylation of ß-catenin’s serine 45 residue carried out by CK1 alpha. This activates GSK-3ß which now phosphorylates ß-catenin at the three neighbouring residues, threonine 41, serine 37, and serine 33 [21;22]. ß-Catenin becomes thus marked for poly-ubiquitination and subsequent degradation through the 26S proteasome pathway [23]. Hence, in the absence of a Wnt-signal intracellular levels of ß-catenin, the key mediator of WS, are kept at low levels.

Activation of the receptor through binding of a Wnt-ligand, however, leads to phosphorylation of the regulatory dishevelled protein which, through its interaction with axin, prevents glycogen synthase kinase 3ß from phosphorylating ß-catenin [24] leading to its stabilization and subsequent nuclear translocation. Within the nucleus, ß-catenin interacts with members of the Lef-1/TCF family and generates a functional transcription factor complex that causes transcriptional activation of certain target genes including c-myc and cyclin D1 [25;26]. In the absence of the Wnt-signal (and ß-catenin), TCF acts as a repressor of Wnt target genes [27-29]. The numerous members of the canonical Wnt-pathway and their interactions have been reviewed in more detail by Roel Nusse et al.,”The Wnt gene Homepage” (http://www.stanford.edu/~rnusse/Wntwindow.html).

Stabilization and accumulation of ß-catenin protein has been identified as a key oncogenic step in the development of various types of cancer. It may result from activating mutations in CTNNB1 itself. These mutations usually occur adjacent to or among the four regulatory phosphorylation sites (Codon 33, 37, 41, 45) located in the NH2-terminus of the ß-catenin protein. Such mutations are causatively associated with colon carcinogenesis [30;31] but have also been identified in human cancers derived from skin [32;33], liver [34], ovary [35], prostate [36], and endometrium [37]. Inactivating mutations in genes encoding proteins that build up the ß-catenin destruction complex have also been found. For example, APC is frequently mutated in hereditary and non-hereditary colon cancers lacking ß-catenin mutations [38;39] and AXIN1 is mutated in hepatocellular carcinomas [40]. The common result of mutation of either gene is the stabilization of ß-catenin and its translocation into the nucleus where it causes transcriptional activation of genes crucial for tumorigenesis. Recent studies mentioned above demonstrate that the aberrant activation of the Wnt signaling pathway plays also an important role in the etiology of certain pediatric malignancies.

3. Hepatoblastoma

Background
Hepatoblastoma (HB) is a rare malignant tumor of the liver with a world-wide incidence of 1.5 cases per million children. It accounts for 60 to 80% of all hepatic tumors in children and therefore it represents the most common type of pediatric liver tumor.

HBs originate from bipotential liver precursor cells, hepatoblasts, that are induced to form through specific molecular interactions between the cardiac mesenchyme and gut endoderm during early liver development [41]. The hepatoblasts proliferate and differentiate into either a biliary epithelial cell or a hepatocyte lineage [42;43]. As a result of their stem cell origin, HBs often present morphological features of both lineages, e.g. areas of tubular differentiation that resemble proliferating bile ductules, or areas that may express markers of hepatocyte differentiation, e.g. albumin. When a neoplastic mesenchymal component accompanies the epithelial elements in hepatoblastomas, the tumor is referred to as a mixed epithelial and mesenchymal HB [44]. Occasionally, mixed hepatoblastomas may contain elements of heterologous differentiation, e.g. muscle, bone and cartilage [45].

The potential role of the Wnt signaling pathway in normal liver development has not been investigated intensively. More recent evidence, however, based on antisense inhibition of ß-catenin in vitro has implicated the Wnt-pathway in embryonic liver cell proliferation [46].

Genetics
Most cases of HB are sporadic, but sometimes it is found to be associated with familial syndromes like Beckwith-Wiedemann syndrome (BWS) [47], an overgrowth syndrome comprising exomphalos, macroglossia, and hemihypertrophy [48;49], or familial adenomatous polyposis coli (FAP) [50;51].

BWS has been linked to chromosome 11p15.5 [52;53], a chromosomal region which is frequently lost in sporadic HBs [54-56]. This LOH has been shown to be uniquely of maternal origin [55], indicating a role for genomic imprinting in the disease. In accordance with this, loss of imprinting of the maternally imprinted insulin-like growth factor 2 gene (IGF2), located on 11p15.5, has been found [57;58]. whereas loss of imprinting of the adjacent but reciprocally imprinted H19 was found only in one case [59] but not in others [57;58].

LOH and CGH studies have identified a number of other chromosomal changes found in HBs, the commonest being loss of 1p [60] and gains of 1q, 2, 8q, 17q and 20 [61;62]. Only rarely mutations of P53 have been detected [63].

HB and the Wnt signaling pathway
An association between HB and familial adenomatous polyposis was described by Kingston et al. [64]. Patients affected with FAP (and which bear a germline mutation of APC) are now known to bear a pronounced increased relative risk for the development of HB which is approximately a thousand times higher than that of the general population [65;66]. Although APC mutations have also been described in HBs of members of FAP kindreds [67], somatic loss or mutation of both APC alleles in such cases have not been reported.

Studies investigating the role of APC mutations in sporadic cases of HB yielded somewhat conflicting results. Somatic mutation resulting in biallelic inactivation of APC has been found in several sporadic cases of HB in one study from Korea [68] and in two studies from Japan [69;70] but such mutations were absent in another independent japanese patients cohort [71]. Two studies in western countries also failed to detect any APC mutation [72;73]. In summary, the different frequencies of APC mutations observed in sporadic HBs seem not to be simply a matter of eastern/western descent, but may be explained by some other variations in the different patients cohorts or, alternatively, by differences in the sensitivity of detection. Wei et al. for example did search for truncating mutations which have been only infrequently observed in a former study [70], and they did so only in a relatively small set of four HB selected for the absence of ß-catenin mutations. In the much larger analysis done by Koch et al. who also failed to detect APC mutations the region of APC analyzed and the method of detection have not been described [72]. For these reasons the true contribution of APC mutations to the genesis of sporadic HB is difficult to assess.

In contrast to the relatively rare occurrence of APC mutations a number of studies to date have reported a high proportion of up to 75% of ß-catenin mutations in HBs [68;71-77] which is among the highest frequencies of ß-catenin mutations reported from any tumor type. About half of the mutations were pointmutations within exon 3 of CTNNB1 resulting in single amino acid changes (figure 2). The mutations affected either one of the four regulatory phosphorylation sites (codon 31, 37, 41, 45) directly or residues immediately flanking codons 33 and 37. It is assumed that the latter mutations are fully equivalent in terms of inhibiting the phosphorylation of ß-catenin through GSK-3ß. Furthermore, HBs are characterized by a rather high prevalence (50%) of relatively large in-frame deletions which result in simultaneous loss of all four regulatory phosphorylation sites. Similar mutations have only rarely been reported from other tumors.

In addition to APC and ß-catenin mutations there may be a low incidence of HBs displaying mutational inactivation of AXIN1, which encodes another important component of the ß-catenin degradation complex [76;78]. The precise functional consequences of these mutations are, however, not yet fully established.

Fig. 2. Distribution of ß-catenin mutations among sporadic cases of hepatoblastomas (HB), nephroblastomas (NB), medulloblastomas (MB), and pancreatoblastomas (PB). The wild-type ß-catenin protein sequence is shown encompassing the four regulatory glycogen synthase kinase-3ß phosphorylation sites highlighted in bold. The amino acid substitutions as were reported in the different studies reviewed here are given above each line. Codon 45 mutations in Wilms tumors are spread into two columns. F.S.; frame-shift mutation.

4. Nephroblastoma

Background
Wilms tumor, or nephroblastoma (NB), is the most common pediatric cancer of the kidney, affecting 1 in 10,000 children. Most cases occur before the age of 5 yrs; the incidence of bilateral involvement is about 5- 10% [79].

Wilms tumors are thought to arise from metanephric blastemal cells that during normal kidney development are induced by the outgrowing ureteric bud to proliferate and differentiate into renal tubular epithelial cells and glomeruli, the functional components of the mature nephron [80]. At this time when kidney formation takes place, Wnt-4 is required for the transition of metanephric blastema to renal epithelial cells [4], providing unambiguous evidence for the involvement of the Wnt signaling pathway in this particular developmental process. Histopathologically, Wilms tumors are reminiscent of embryonic nephrogenesis and comprise undifferentiated blastemal cells, differentiated epithelial cells and stromal cells; ectopic components, particularly skeletal muscle, may also be observed occasionally [81].

Genetics
There are several malformation syndromes predisposing to Wilms tumors. In patients with BWS the risk of developing Wilms tumor is about a thousandfold increased [82]. As is the case for HBs, it is always the maternal allele of the BWS gene located at 11p15 that is also frequently lost in Wilms tumors [83-85]. Furthermore, loss of imprinting (LOI), leading to increased expression of the normally monoallelically expressed IGF2 gene, can be regularly observed in Wilms tumors [86] and has been linked to methylation-induced silencing of the H19 gene on the same chromosome [87;88].

Patients suffering from WAGR syndrome (Wilms tumor, aniridia, genitourinary abnormalities and mental retardation), carry constitutive deletions of chromosome 11p13 [89], a region encompassing the Wilms tumor supressor gene WT1 [90;91]. In most cases, allelic loss of WT1 is accompanied by pointmutational inactivation of the second allele in WAGR-associated Wilms tumors but also in about 6 to 25% of sporadic Wilms tumors [92-94]. Finally, dominant mutations of WT1 may confer an elevated risk to develop Wilms tumors in the setting of Denys-Drash [95], a malformation syndrome which is otherwise characterized by mesangial sclerosis and male pseudohermaphrodism [96;97].

Besides the BWS-associated Wilms tumor suppressor gene at 11p15 and the WT1 gene at 11p13 additional Wilms tumor suppressor genes have been inferred by non-random allelic losses found at 16q [98;99] and 1p [100;101]. Finally, mutations of P53 have been found in a subset of WTs and are associated with an anaplastic histology and poor prognosis [102].

NB and the Wnt signaling pathway
Aberrant activation of the Wnt signaling pathway in Wilms tumors has so far been limited to mutations in CTNNB1. In three independent studies 33 (15%) ß-catenin mutations have been identified among a total number of 217 cases studied [93;103;104]. Interestingly, the vast majority of these mutations (28 of 33) affected serine 45, which identifies codon 45 as an important mutational hot-spot in Wilms tumors. The mutations comprised either single nucleotide changes or small interstitial deletions which result in complete loss of serine 45. Of particular importance is the fact that ß-catenin mutations were found in tumors harbouring concomitant lesions in WT1 [93;103]. Thus, WT1 and ß-catenin probably act synergistically together during Wilms tumorigenesis. In subsequent studies, Maiti et al. found that ß-catenin mutations occur almost invariably in the presence of WT1 mutations [93;103]. Given the relatively low abundance of both WT1 and ß-catenin mutations these findings were highly significant and one may predict now that tumors showing WT1 but no ß-catenin mutations might harbour genetic lesions in other members of the Wnt signaling pathway. It is possible that these lesions involve APC, because LOH of 5q21, the APC locus, has been found, although infrequently, in Wilms tumors [105;106]. Analysis of 22 Wilms tumors did not reveal any mutation of AXIN1 [107].

In retrospect, it is rather surprising that patients with germline mutations of APC, which are genetically predisposed for rapid somatic acquisition of aberrant WS, do not seem to be at an increased risk to develop Wilms tumors (H.T. Lynch, personal communication). This may be explained by some kidney-specific differences in the ß-catenin regulation through APC. Alternatively, FAP patients are indeed at an increased risk to develop Wilms tumors but the relative risk is too low yet to be detected by the comparatively low number of cases reported.

5. Medulloblastoma

Background
Medulloblastoma (MB) is a malignant embryonal tumor of the cerebellum and the most common malignant brain tumor in children. The peak incidence is between 5 and 10 years of age with boys being slightly more frequently affected than girls [108]. MB belongs to the group of primitive neuroectodermal tumors (PNET).

Medulloblastomas are most likely derived from pluripotential neuronal stem cells present in the external granular layer (EGL) of the developing cerebellum [109] which before they differentiate into glial and neuronal cell lineages undergo a dramatic expansion in cell number during the early phases of postnatal brain development [110]. The massive proliferation of granule cell precursors is stimulated by signals sent out by their future postsynaptic regulatory partners, the Purkinje cells, which themselves are derived from a second proliferative compartment within the developing cerebellum, the ventricular neuroepithelial zone. Signals exchanged between cells derived from both the EGL and the ventricular zone orchestrate the diverse morphogenetic processes, e.g. proliferation, migration, differentiation, involved in the formation of the mature cerebellum. The molecular basis of these signals is largely unknown but may include members of the sonic hedgehog as well as the Wnt family [2;111].

As a consequence of their stem cell origin MB may display neuronal as well as glial differentiation side-by-side [112]. Occasionally, one can find atypical differentiation along myoblastic or even melanocytic lineages.

Genetics
Although the majority of medulloblastomas occur sporadically, some manifest within familial cancer syndromes including Gorlin syndrome and FAP [113-115]. Heterozygous mutations of the human patched gene are associated with Gorlin syndrome [116] and low frequencies of mutation of patched have also been found in sporadic cases of MB [117-119]. MBs may also present as an extracolonic manifestation of FAP in patients with Turcot syndrome [115;119;120].

Studies on loss of heterozygosity (LOH) have found loss of 17p in about 30 % of MBs. [121-123]. Mutations of p53 gene, which is located on 17p13, have been found, however, in only 5-10 % of MBs [124;125] suggesting the existence of at least another tumor suppressor gene in this region.

MB and the Wnt signaling pathway
A familial association of colon polyps and brain tumors, either glioblastoma multiforme or medulloblastoma, is found in patients with Turcot’s syndrome. Families who develop predominantly glioblastomas typically inherit germline mutations of DNA mismatch repair genes whereas Turcot’s patients with MB have been shown to harbour mutations in APC [126;127]. Despite these associations, however, it remained for a long time a matter of controversy whether or not the APC mutations found in Turcot’s patients really contributed to the development of medulloblastomas or if the occurrence of MBs in patients with FAP was rather coincidential. The findings of somatic loss of the second APC allele in a medulloblastoma of a Turcot’s patient [126] and of APC mutations in sporadic cases of MB [128;129], however, strongly favour a direct role of APC. It is important to note that the APC mutations which have been reported in MBs are exclusively point mutations and that LOH at 5q (the APC locus) is virtually absent in FAP-associated [127] as well as sporadic MBs [130]. Thus, there seems to be a small probability that haploinsufficieny for APC may predispose for MBs without the requirement to loose the second allele. Since ß-catenin mutations, which also activate the Wnt-pathway, do occur in medulloblastomas, it is yet unlikely that the APC mutations of Turcot’s patients play no role in the development of MBs.

Mutations of CTNNB1 in MBs have been investigated in several independent studies [128;129;131-133] and a total number of 15 mutations (6%) among 267 cases has been detected (figure 2). 14 mutations were missense mutations and affected either codon 33 (nine cases), codon 37 (three cases), or codon 32 (two cases). One mutation was a single nucleotide deletion that was reported in codon 49 [131], however, such a mutation should cause a frame-shift of the ß-catenin protein. It is difficult to understand how this mutation may exert a domi-nant negative effect. Therefore, the significance of this finding is not clear.

There are also two recent studies which have analyzed the possible involvement of Axin1 mutations in MB. Dahmen et al. found one point mutation (Pro255Ser) and seven large deletions in 86 MBs analyzed [134], and Baeza et al. found two point mutations in 39 MBs (Pro255Ser and Ser263Cys) and five large deletions [135]. The latter deletions have, however, been questioned because they have been found only by RT-PCR analysis and could not been verified at the genomic level. Furthermore, similar deletions were found by RT-PCR in normal tissue of the patients. These findings led to the suggestion that reverse transcriptase induced template switching might have caused these deletions artificially at endogenous sites containing direct repeats [135].

6. Pancreatoblastoma

Background
Pancreatoblastoma (PB), although the most common pancreatic neoplasm in childhood, is exceedingly rare with only about 60 reported cases world-wide. Pancreatoblastoma, like all other blastomas of childhood, affects children in the early years of life. Most patients are younger than eight years and boys are slightly more frequently affected than girls [136].

Pancreatoblastomas arise from pluripotential pancreatic stem cells capable of differentiating along all major pathways found in the pancreas juxtaposing exocrine acinar and ductal cells as well as endocrine cells. Thus, these embryonal tumors recapitulate the normal embryogenesis of the pancreas, during which epithelio-mesenchymal interactions play a similar important role as in liver and kidney development [137;138] As such pancreatoblastomas are fully analogous to other embryonal neoplasms like Wilms tumors or hepatoblastomas. Unfortunately, the potential role of the Wnt signaling pathway during normal pancreatic development has not been addressed specifically. A recent study demonstrated, however, that several Wnt-family members are expressed in embryonic pancreas and that aberrant stimu-lation of the Wnt signaling pathway in the pancreatic anlagen by overexpression of Wnt1 severly disturbs the normal architecture of the developing pancreas in transgenic mice [139].

Genetics
Due to the extreme rarity of this neoplasm, only little is known about the molecular pathways leading to pancreatoblastoma. Similarly to hepatoblastomas and Wilms tumors, however, pancreatoblastomas sometimes arise in the context of Beckwith-Wiedemann syndrome [140-143]. In both nephro- and hepatoblastomas, loss of the maternal allele, from which H19 but not IGF2 is expressed, is frequently found, and in accordance with this, maternal-specific LOH of 11p15.5 has also been demonstrated in a case of pancreatoblastoma [144].

PB and the Wnt signaling pathway
The first patient with FAP and germline mutation of APC who developed a pancreatoblastoma was recently described [145]. The PB displayed tumor-specific LOH at 5q suggesting that the germline mutation of APC predisposed and that somatic loss of the second allele contributed to the development of PB in this patient. In eight cases of pancreatoblastoma in patients without FAP, however, no mutations of APC were detected but, instead, in five of them prototypic ß-catenin mutations were found. The mutations were single nucleotide changes affecting codons 32 (twice), 33, 34, and 37 (figure 2). In another study, Tanaka et al. detected ß-catenin mutations in two of five pancreatoblastomas but no APC mutations [146]. The ß-catenin mutations found affected codon 33 and 37, respectively. From these findings it appears that ß-catenin mutations, and mainly those affecting the codon 33/37 cluster region, are present in a significant proportion of PBs, and it seems likely that mutations affecting other members of the Wnt-pathway will soon emerge.

Of note, Kerr et al. reported a case of pancreatoblastoma displaying mutation of CTNNB1 and concomitant loss of 11p15 material in a patient presenting with BWS-like overgrowth symptoms. This which may suggest non-redundant effector mechanisms caused by the observed molecular events [147].

7. Summary
When reviewing the available data it becomes apparent that solid childhood tumors arising in the liver, the kidney, the brain, and the pancreas, although originating from entirely different precursor cells, have some important features in common (table 1).

Table 1: The Wnt signaling pathway in solid childhood tumors

Malignancy	hepatoblastoma	medulloblastoma	nephroblastoma	pancreatoblastoma
Incidencea	1.5	5 (Fc) / 8.6 (Mc)	7.3	<1
Peak age at diagnosis	<2 yrb	7 yr	2 yr	unknown
Association with FAPd	yes	yes	no	1 FAP patient
Mutations found in sporadic cases:
CTNNB1e
percentage	55%	6%	15%	62.5%
cases reported	116/210	15/267	33/217	5/8
APC
percentage	6%	1.5%	unknown	unknown
cases reported	7/124 (only 1 study (7/20 cases) positive)	3/200
AXIN1
percentage	7%	2%	0%	unknown
cases reported	2/27	3/125	0/22

^a annual rate per million , age < 15yr; data from Ries LAG, Eisner MP, Kosary CL, Hankey BF, Miller BA, Clegg L, Edwards BK (eds). SEER Cancer Statistics Review, 1973-1999, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1973_1999/, 2002
^b yr, year;
^c F/M, female/male;
^d FAP, familial adenomatous polyposis coli
^e CTNNB1, ß-catenin gene

HBs, NBs, MBs, and PBs are all derived from rapidly dividing stem cells, which during embryonic development are programmed to undergo a massive but transient boost of proliferation. In tumor cells this state of high proliferation is locked, and that’s probably the reason why embryonic tumors are usually so fast growing. Few of these childhood cancers carry mutations in P53, a common event in epithelial cancer in adults. This may partially explain the high sensitivity of childhood tumors to chemotherapy because wildtype p53 maintains apoptotic mechanisms important for chemotherapy-induced cell death.

In each embryonic cancer, the precursor cells are most likely bi- or even multi-potential stem cells which during development give rise to at least two different cellular lineages within a given organ. This stem cell derivation is remarkably reflected by the broad spectra of histopathological appearence HBs, NBs, MBs, and PBs typically present. All of these recapitulate the embryogenesis of the organ from which they originated. They display features of differentiation from the different lineages, at different stages of development and occasionally may show differentiation even along heterologous lineages suggesting a stem-cell of origin with even broader specificity.

Proper organ development requires extensive cell-to-cell signaling to ensure that cell proliferation, migration, and differentiation occurs in a well-coordinated fashion. Although the potential role of the Wnt signaling pathway is not perfectly established in each of the organs discussed (yet in the kidney and the brain it is), common mutations affecting crucial members of this pathway which are found in HBs, NBs, MBs, and PBs, strongly implicates the Wnt-pathway in each of the underlying developmental processes.

The major mutational target gene within the Wnt signaling cascade which is affected in HBs, NBs, MBs, and PBs, is CTNNB1, whereas in adult colon tumors, for instance, APC shows a much higher prevalence of mutations. Since other adult tumors share the preference for ß-catenin over APC mutations, however, this phenomenon may be specifically related to the colon more than to childhood tumors.

The overall frequency of ß-catenin mutations in HBs, NBs, MBs, and PBs ranges from 6% (MBs) to 55% (HBs). Thus, although the Wnt-pathway plays a causative role in these tumors it does so only in a subset of them. The relative frequency may be underestimated, since immunohistochemical studies on HBs, NBs, MBs, and PBs have shown nuclear accumulation of ß-catenin protein, a marker of an activated Wnt-pathway, in a much higher frequency than ß-catenin or APC mutations are found. There may exist genetic lesions in other members of the Wnt signaling pathway, e.g. AXIN1, which have not yet been identified.

Notably, the mutational spectrum of ß-catenin shows distinctive features among HBs, NBs, MBs, and PBs (figure 2). HBs are characterized by a large proportion of deletions which result in loss of the entire region encompassing the GSK-3ß targeting box. Similar mutations have thus far not been reported from the other childhood cancers. On the other hand, NBs stand out because of their striking high frequency of codon 45 mutations; the vast majority of point mutations in the other tumors cluster around codon 33/37, instead. This amazing mutational distinctiveness may reflect some organ-specific differences in the oncogenic capacity of different ß-catenin mutations. Indeed, using rat colon tumors induced by the alkylating agent 1,2,-dimethylhydrazine (DMH) we and others previously found convincing evidence that codon 41/45 mutations intrinsically bear a higher oncogenic potential than mutations affecting the codon 33/37 cluster region [148;149] and thus are selected for in the DMH model. Whether this situation may be similar in human embryonic or adult tumors remains to be established. Alternatively, different mutational patterns of ß-catenin may simply reflect the involvement of distinct carcinogenic pathways. Testing this hypothesis may eventually lead to the identification of specific environmental factors which are responsible for cancer development in an apparently tissue-specific manner.

As would be expected, HBs and MBs occur at elevated frequencies in patients with a germline mutation of APC. And although only one case of PB has been described in the setting of FAP, given the rarity of both diseases, this association may also be present in PBs. FAP patients do not show, however, a predisposition for NBs, which is surprising. Similarly, HBs, NBs, and PBs are associated with BWS, but MBs are not (J. B. Beckwith, personal communication), although an essential role of IGF2, a key molecule involved in BWS, for the development of MBs has been established in a transgenic mouse model [150]. It will be interesting to see whether both these pictures, the apparent lack of association between FAP and NBs and between BWS and MBs, may change with time and with more cases being collected.

The recent elucidation that mutational activation of the Wnt signaling pathway plays an important role in diverse solid pediatric tumors opens up new avenues for future research and may even allow for the development of more specific, less toxic drugs for anticancer therapy. Mutant ß-catenin epitopes may for example provide attractive target molecules for tumor-specific, active immunotherapy since it is known that cytotoxic Tcells recognizing mutant but not wild-type ß-catenin can be induced in patients [151]. The use of replicating adenoviruses that target tumor cells with constitutive activation of the Wnt signaling pathway may represent a promising alternative approach [152;153]. Full benefit from such strategies, however, awaits identification of those other components within the Wnt signaling cascade which are different from ß-catenin, APC, and axin, and which are yet unknown players in the carcinogenic process that is able to drive tumor development in young children.

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