American Journal of Medical Genetics Part C (Semin. Med. Genet.) 129C:29 – 34 (2004) A R T I C L E Familial Wilms Tumor E. CRISTY RUTESHOUSER AND VICKI HUFF* Wilms tumor (WT), an embryonic tumor arising from undifferentiated renal mesenchyme, has been a productive model for understanding the role of genes in both tumorigenesis and normal organogenesis. Approximately 2% of WT patients have a family history of WT, and even sporadic WT is thought to have a strong genetic component to its etiology. Familial WT cases generally have an earlier age of onset and an increased frequency of bilateral disease, although there is variability among WT families, with some families displaying later than average ages at diagnosis. One WT gene, WT1 at 11p13, has been cloned, but only a minority of tumors carry detectable mutations at that locus, and it can be excluded as the predisposition gene in most WT families. Two familial WT genes have been localized, FWT1 at 17q12–q21 and FWT2 at 19q13.4; lack of linkage in some WT families to either of these loci implies the existence of at least one additional familial WT gene. Originally modeled as the inheritance of a mutation in a tumor suppressor gene, molecular analysis of familial tumors not linked to 11p13 have provided data suggesting that this model may be overly simplistic and/or not applicable to all WT families. Identification of the FWT1 and FWT2 genes will help clarify this and will also likely aid in our understanding in general of the roles of the various WT genes and their genetic interactions in the development of WT. ß 2004 Wiley-Liss, Inc. KEY WORDS: Wilms tumor; WT1; FWT2; FWT1 INTRODUCTION Wilms tumor (WT) is a childhood cancer of the kidney that arises from undifferentiated fetal mesenchyme and is diagnosed in about 1 in 10,000 Caucasian children. Tumors typically display a variable triphasic histology of blastemal, epithelial, and stromal elements, suggestive of incomplete and aberrant differentiation of the fetal mesenchyme. The prognosis for most children diagnosed with WT is good, with a long-term E. Cristy Ruteshouser is a Research Scientist in the Section of Cancer Genetics, Department of Molecular Genetics, at The University of Texas M. D. Anderson Cancer Center, Houston, Texas. She is currently pursuing the identification of the FWT2 gene located on chromosome 19q. Vicki Huff is an Associate Professor in the Section of Cancer Genetics, Department of Molecular Genetics, at the University of Texas M. D. Anderson Cancer Center, Houston, Texas. She has a long-standing research program in the genetics of Wilms tumor and the role of WT1 in Wilms tumor. *Correspondence to: Vicki Huff, Ph.D., Department of Molecular Genetics, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030. E-mail: email@example.com DOI 10.1002/ajmg.c.30025 ß 2004 Wiley-Liss, Inc. survival rate of over 90% for localized disease and over 70% for metastatic disease [Grosfeld, 1999]. WT with diffuse anaplasia, however, is more resistant to conventional therapy and is associated with a poorer prognosis. Most cases of WTare sporadic (98– 99%) and unilateral (90–95%). Congenital anomalies, such as aniridia (AN) and genitourinary anomalies (GU), are observed in &1% and &3% of all WT cases, respectively. Somatic overgrowth syndromes, e.g., Beckwith-Wiedemann syndrome (BWS) and Simpson-GolabiBehmel syndrome (SGB), and hemihypertrophy are observed in another &4% of patients [Breslow et al., 1993]. WT, along with GU anomalies (notably male pseudohermaphrodism) and renal mesangial sclerosis resulting in early onset renal failure, is also a feature of DenysDrash Syndrome. The average age of WT diagnosis is 42–47 months for children with unilateral tumors and 30–33 months for children with bilateral disease [Breslow et al., 1993]. An earlier age at diagnosis and an increased frequency of bilateral disease is also observed in children with congenital anomalies, and also, with some notable exceptions, in WT families [Knudson and Strong, 1972; Breslow et al., 1993]. These data suggest that patients with congenital anomalies or familial WT carry a germline mutation that predisposes to the development of multiple tumors at an earlier age than in the general population, as is the case with individuals with other types of cancer predisposition syndromes, who exhibit early diagnosis and multiple tumors [Knudson and Strong, 1972]. As an embryonal tumor, WT has been of interest to both developmental biologists and geneticists as a model for understanding normal kidney development and for understanding the role of genetic alterations in tumorigenesis. Unlike most adult tumors, WT is a relatively euploid cancer [Wang-Wuu et al., 1990; Maw et al., 1992], with no strong environmental exposure implicated in its development. These features, in addition to its genesis in proliferating undifferentiated tissue, suggest that the number of genetic alterations required for tumorigenesis may be fewer than in adult tumors and that the alterations that are present are significant events. That WT provides a tractable model for understanding the role of genetic alteration in tumor development is underscored 30 AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) by the fact that the study of WTwas key in the development of the two-hit, tumor suppressor gene model for tumorigenesis, which has become the underlying framework for developing hypotheses on the role of genetic alterations in both childhood and adult cancers. Molecular studies of WT have also provided other precedents in cancer genetics, such as genetic heterogeneity in tumor predisposition, a role of imprinted genes in tumor development, and the recognition that a ‘‘cancer’’ gene can also play a key role in normal development [Knudson and Strong, 1972; Schroeder et al., 1987; Grundy et al., 1988; Huff et al., 1988; Reik and Surani, 1989; Kreidberg et al., 1993; Ogawa et al., 1993; Rainier et al., 1993]. FAMILIAL WILMS TUMOR Approximately 2% of Wilms tumor patients have a family history. Approximately 2% of Wilms tumor patients have a family history. The overwhelming majority of WT families are small, with just two or three affected members. A hallmark of WT families is the presence of affected individuals, often cousins or siblings, who are related through an unaffected obligate carrier of the predisposition allele; affected parentchild pairs are observed in only &10% of familial cases [Breslow et al., 1996]. Studies of pedigrees and segregation analyses have suggested that WT predisposition is the result of an autosomal dominant allele that is incompletely penetrant, and the penetrance of such alleles has been estimated to be between 25 and 60% [Brown et al., 1972; Knudson and Strong, 1972; Matsunaga, 1981]. Males and females are equally represented in the affected individuals. A gender bias is also not observed in the obligate carrier parents of affected children, indicating that the segregating predisposition gene is not subject to parent-of-origin (imprinting) effects [Breslow et al., 1996]. Consistent with the inheritance of a predisposing mutation, an increased frequency of bilateral tumors and a concomitant earlier age of diagnosis is observed in familial cases overall. The average age of onset for familial WT is &35 months for unilateral tumors and 16 months for bilateral disease, which occurs in &16% of familial cases [Breslow et al., 1996]. Figure 1 shows a pedigree of a large WT family that displays the increased frequency of bilateral disease, the early age of diagnosis, and the presence of unaffected obligate carriers that are general features for familial WT. Interestingly, however, WT families appear to be heterogeneous with regard to penetrance, frequency of bilateral disease, and age at diagnosis [Breslow et al., 1996]. This observation may be attributable to locus heterogeneity, allelic heterogeneity, and/or the action of a modifying or interacting gene(s). Even when the same locus is involved, variability is observed. For example, of four large families linked to a predisposition locus at 19q13.4, one shows early WT onset (average 17 months), one shows late onset (average 97 months), and one displays the unusual feature of neural ARTICLE elements in the tumors from all four affected individuals [Hussong et al., 2000] (Table I). These data are suggestive of allelic heterogeneity and/or the effect of modifying genes. In rare instances, WT cases have been reported in the context of other familial syndromes. These include familial cancer syndromes (Bloom syndrome, Li-Fraumeni syndrome, neurofibromatosis Type 1, and hyperparathyroid-jaw tumor syndrome) in which isolated cases of WT have been observed [Cairney et al., 1987; Hartley et al., 1993; Perilongo et al., 1993; Kakinuma et al., 1994]. WT is also observed, as noted above, in the somatic overgrowth syndromes, BWS and SGB. Most notably, approximately 4% of children with BWS develop WT, and another &4% of BWS patients develop other embryonal malignancies [Wiedemann, 1964; Beckwith, 1969; Sotelo-Avila et al., 1980; Wiedemann, 1983]. Mutation or altered expression of one or more genes in a cluster of imprinted genes at 11p15 has been observed in BWS [reviewed in Li et al., 1998], and many of these genes play a role, either positively and negatively, in growth control. These data, along with the observation of nephrogenic rests—foci of undifferentiated Figure 1. Pedigree of 19q13.4-linked family WTX524, showing incidence of WT in this family. Age (in months) at diagnosis for each affected individual is indicated. The arrow indicates the proband. ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) TABLE I. Variability of Clinical Features of WT Families Linked to FWT2 at 19q13.4 Family Mean age (months) at diagnosis (range) % Bilaterality Histology WTX524 WTX593 WTX614 WTX917 16.6 months (4–37) 43.5 months (37–57) 96.5 months (39–204) 30.0 months (7–66) 25% (2/8) 0% (0/4) 17% (1/6) 0% (0/4) Triphasica Triphasic Triphasic Triphasic with neural elementsb a Huff . Hussong et al. . b embryonic cells—in WT patients both with and without BWS imply that perturbation of normal growth and differentiation of the embryonic kidney plays a role in WT development [Beckwith, 1998]. Familial WT patients, however, only rarely display features of the above genetic syndromes. The most common, BWS, is noted in only &3% of the WT families in the National Wilms Tumor Study (NWTS) population-based registry [Breslow et al., 1996]. Similarly, an excess of tumors other than Wilms tumor was not observed in WT families in this registry [Felgenhauer et al., 2001]. Thus, although some genetic syndromes are associated with WT, the association is primarily with sporadic WT, not familial WT. WILMS TUMOR GENES The etiology of Wilms tumor is genetically heterogeneous. The etiology of Wilms tumor is genetically heterogeneous. Although WT was originally assumed to be due to alteration of a single gene, it is now known that several genes can play roles in WT development or progression. The only WT gene isolated to date, however, is WT1, which was first localized by virtue of the observation of 11p13 germline deletions in WT/AN patients [Francke et al., 1979]. WT1 Subsequent cloning of the 11p13 gene, WT1, revealed that it encodes a 449–amino acid protein containing four zinc finger motifs and a regulatory domain and that it is a member of a large family of zinc finger transcription factors [Call et al., 1990; Gessler et al., 1992]. The WT1 transcript is alternatively spliced, resulting in four isoforms and four protein products that differ in their capacity to regulate gene expression. Many genes have been shown to be transcriptionally activated or repressed by WT1 [reviewed in Lee and Haber, 2001], but it is still not clear which genes’ dysregulation is essential for tumor development following WT1 mutation. A recent gene expression profiling study of Wilms tumors has demonstrated upregulation of c-myc expression in association with mutations in WT1, but dysregulation of additional target genes is likely also important [Udtha et al., 2003]. Since many of the genes putatively repressed by WT1 function to promote cell proliferation, a logical model for the role of WT1 in tumorigenesis is that inactivation of WT1 results in increased expression of these growth stimulatory genes. The association of AN and WT is now known to be due to deletion of two distinct genes. In contrast, patients with WT and GU abnormalities often carry germline WT1 mutations [Pelletier et al., 1991a; Huff et al., 1991b]. Tumors from germline mutation carriers invariably have sustained inactivating mutations in both WT1 alleles [Huff, 1998], consistent with the model of WT1 as a 31 tumor suppressor gene. A reduction to homozygosity for somatic WT1 mutations is also observed in tumors from genotypically normal individuals. WT1 mutations described to date are predominantly deletion or truncation mutations, although missense mutations at codons encoding amino acids thought to be functionally critical within the zinc finger domains are also observed, most notably in patients with Denys-Drash syndrome [Pelletier et al., 1991b]. Interestingly, germline mutations that result in altered ratios of normal splice isoforms are observed in patients with a triad of gonadoblastoma, GU anomalies, and later onset renal failure (Frasier Syndrome) [Barbaux et al., 1997]. Germline WT1 mutations are usually de novo mutations. Germline WT1 mutations are usually de novo mutations. WT1 mutational analysis of familial cases demonstrated that only 2 out of 30 families carried an inherited alteration in WT1 [Huff, 1998]. Germline WT1 mutations have been identified in WT patients with no family history. Analysis of parental DNA from 14 such patients revealed that in only one case was the mutation also present in the parent; the remaining 13 germline mutations had arisen de novo (Huff, unpublished data). Thus, germline WT1 mutations are rarely observed in a family context, and most individuals with germline WT1 mutations are ‘‘sporadic’’ cases. Analysis of tumor DNA from these patients demonstrates that, as originally reported, tumors are homozygous for the paternally-derived allele, indicative of a paternal origin of the WT mutation, similar to the predominantly paternal origin of large de novo 11p13 deletions [Huff et al., 1991a; Huff, 1998]. By genetic linkage analysis of WT families, WT1 can be excluded as the predisposition gene segregating in most WT families [Grundy et al., 1988; Huff et al., 1988]. Although unexpected at the time, now that GU anomalies are 32 AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) known to be a consequence of germline WT1 mutation, the infrequent role of WT1 in familial predisposition is not surprising, given the paucity of GU anomalies in WT families. Similar to the results of the linkage analyses, direct sequence analysis of WT1 in both large and small WT families has indicated that WT1 mutation is rare, being observed in one study in only 3 out of 30 WT families [Huff, 1998], with additional isolated case reports [Pelletier et al., 1991a; Kaplinsky et al., 1996; Pritchard-Jones et al., 2000]. Other WT Genes Mutation of two genes known for their critical role in other types of tumors, p53 and the b-catenin gene, is observed in 5% and 15% of Wilms tumors, respectively [Bardeesy et al., 1994; Koesters et al., 1999; Maiti et al., 2000]. p53 mutation is strongly associated with an anaplastic tumor histology and poor prognosis [Bardeesy et al., 1994], and b-catenin mutation is strongly associated with additional mutation at the WT1 locus [Maiti et al., 2000]. For both genes, the observed mutations are somatic events, and there is little evidence to suggest that either gene plays a role in familial WT. Alteration of a number of other genes/genomic regions has been implicated in WT development by the observation of genomic regions displaying loss of heterozygosity (LOH) in tumors. Unlike adult tumors, Wilms tumors display very little (<5%) ‘‘background’’ LOH [Wang-Wuu et al., 1990; Maw et al., 1992]. Thus, the observation of LOH at 11p, 16q, 1p, and 7p in 40%, 20%, 20%, and 15% of tumors, respectively, identified additional regions of the genome that may harbor genes important in tumor development. In some tumors, 11p LOH is confined to markers at 11p15, a region (as noted above) known to contain a cluster of imprinted genes that play roles, either positively or negatively, in growth control. One such gene whose product positively regulates growth and proliferation, IGF2, is expressed only from the paternally-derived allele. The observa- tion of LOH and loss of maternal 11p15 alleles in normal kidney as well as in tumors, as a result of somatic recombination, suggests that loss of maternallyderived alleles and/or duplication of paternally-derived 11p15 alleles (including paternally-expressed IGF2 alleles) results in a growth advantage for both normal and malignant cells [Chao et al., 1993]. The observation that tumors that do not display 11p15 LOH often alternatively show loss of imprinting (LOI) [Ogawa et al., 1993; Rainier et al., 1993] further underscores the notion that, similar to BWS, altered expression of normally imprinted genes is an important feature in the development of many Wilms tumors. However, for the various genomic regions displaying LOH there is little data implicating genes at any of these regions as playing a role in familial predisposition, and for 11p15 and 16q there are data ruling out these regions as harboring familial predisposition genes in several large families [Grundy et al., 1988; Huff et al., 1992]. Familial Predisposition Genes WT1 mutation is observed only rarely in WT families, and genetic linkage studies of large WT families have been employed to localize genes that more commonly predispose to familial WT. As a result of these studies, Two familial predisposition genes have been mapped to the genome: FWT1 at 17q12–q21 and FWT2 at 19q13.4. two familial predisposition genes have been mapped to the genome: FWT1 at 17q12-q21 [Rahman et al., 1996] and FWT2 at 19q13.4 [McDonald et al., 1998]. Neither gene has yet been identified. There are also WT families for which linkage at any ‘‘WT gene’’ locus can be ruled out, implying that additional predisposition genes have yet to be localized [McDonald et al., 1998; Rahman et al., 1998]. ARTICLE As mentioned above, pedigree and segregation analyses previously suggested that predisposition is the result of an autosomal dominant allele that is incompletely penetrant, and, following the precedent of retinoblastoma and the demonstrated role of WT1 as a tumor suppressor gene, familial predisposition to WT has been modeled as involving a germline mutation that is reduced to homozygosity in tumors. However, molecular data on familial tumors indicate that this may be too simple a model. The first suggestion of this was the observation of LOH at the FWT2 region at 19q13.4 in tumors from families whose inherited predisposition was not linked to FWT2 [McDonald et al., 1998]. As shown in Figure 2, tumors from two WT families show 19q13.4 LOH, but the alleles retained in the tumors are not present in blood DNA of other affected family members. Conversely, of the tumors analyzed to date from members of FWT2-linked families, none display 19q LOH. These data suggest that alterations at two distinct loci are critical rate-limiting steps in tumor development in some families. The observation of 19q LOH in some nonfamilial cases implies that FWT2 also plays a role in sporadic disease. Thus, a two-locus model or a model of a predisposition gene modified by another gene may more accurately reflect the molecular genetics of these 19q-involved tumors. The role of FWT1 in familial predisposition and tumorigenesis also may not conform to original expectations; a tumor from a FWT1-linked family was observed to have lost the 17q alleles genetically linked to predisposition in the family, suggestive of a ‘‘hit-and-run’’ mechanism for the FWT1 predisposition gene [Rahman et al., 1997]. SUMMARY AND DISCUSSION The genetic model for Wilms tumorigenesis has evolved over the years. Originally thought to follow a simple one-locus, ‘‘two-hit’’ paradigm established by retinoblastoma, another childhood tumor, the genetic etiology of WT ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) 33 pensatory pathways in fetal kidney that are present in other tissues. Regardless of whether familial WT genes turn out to play critical roles in a narrow subset or a wide range of cell types, given the novel discoveries that have come out of the study of WTand the unexpected data on familial tumors, the study of WT families is likely to provide further insight into the role in general of WT genes in cancer development and may even identify novel mechanisms by which—or novel cellular pathways in which—genetic alterations result in cancer susceptibility. REFERENCES Figure 2. FWT2 LOH in tumors from WT families unlinked to FWT2. Below each pedigree symbol, the PCR products resulting from amplification of two 19q13.4 polymorphic loci, D19S601 and D19S589, are shown. Alleles retained in the tumors are indicated by arrows. In each family, the allele retained in the tumor is not carried by at least one other affected individual, demonstrating nonlinkage to 19q. Pedigree symbols are as indicated in Figure 1. TT is tumor from the indicated individual. is now recognized to be heterogeneous and more complex. Several genes are now known to play a critical role in the etiology of WT: WT1 at 11p13, FWT1 at 17q12–q21, FWT2 at 19q13.4, and at least one additional familial WT gene. The alteration, primarily somatic, of other genes—11p15 imprinting loci; p53; b-catenin; and other genes at 16q, 7p, and possibly in other genomic regions—also plays a role in tumor development. How, or whether, alterations at multiple ‘‘WT’’ genes act independently or in concert is unknown. With the exception of WT1 and b-catenin mutations that are highly associated with each other, there is little known about the patterns of genetic alterations that occur in tumors. 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