THE GENETICS OF WILMS’ TUMOR Daniel A. Haber*t and David E. Housman* ‘Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 TMassachusetts General Hospital Cancer Center, Charlestown, Massachusetts 02129
I. 11. 111. IV.
V. VI.
VII. VIII.
Introduction Histology and Clinical Considerations T h e Knudson Model Genetic Loci Associated with Wilms’ Tumor A. Chromosome 1 lp13 €3. Chromosome 1 l p l 5 C . Familial Wilms’ Tumor Isolation of the W T l Gene at 1 1p 13 WT1: Characterization of a Novel Tumor Suppressor Gene A. Gene Structure and Alternative Splicing B. Normal Tissue Expression of’WT1 C. WTI Mutations in the Germline and in Wilms’ Tumors Functional Studies and Animal Models Conclusions References
I. Introduction The isolation of the WTI gene involved in the genesis of Wilms’ tumor has provided a new molecular tool to understand the normal and abnormal development of the kidney and related tissues. Wilms’ tumor is pediatric kidney cancer, which arises in 1 in 10,000 children. It can present in both a common sporadic and a rare hereditary form, along with various congenital abnormalities. The existence of both gross chromosomal abnormalities as well as more subtle molecular deletions has led to the genetic characterization of a number of loci involved in the development of Wilms’ tumor. Within one of these loci, band 13 on the short arm of chromosome 11, we have recently isolated a gene, WTI, which is specifically inactivated in Wilms’ tumors. In this article we discuss the complex genetics of Wilms’ tumor, and the initial studies characterizing the role of the WTI gene product in tumorigenesis.
41 ADVANCES IN CANCER RESEARCH, VOL. 5Y
Copyright 0 1992 by Academic Press, Inc. All rights of reproduction in any form resemed.
42
DANIEL A. HABER AND DAVID E. HOUSMAN
II. Histology and Clinical Considerations Wilms’ tumor constitutes some 10% of all pediatric cancer, and is the most common intraabdominal solid tumor in children. The peak incidence is between 3 and 4 years of age, with most children presenting with a palpable abdominal mass. Some 5-10% of patients with Wilms’ tumor have bilateral cancers, and these children tend to present between 2 and 3 years of age (Matsunaga, 1981). Rarely, children with Wilms’ tumor will show evidence of genetic malformations and chromosomal abnormalities (see below). T h e malignant transformation in Wilms’ tumor is thought to originate in cells of the metanephric blastema (Bennington and Beckwith, 1975). This fetal structure is thought to give rise to the genitourinary system, and Wilms’ tumors are characterized by their histologic diversity (see Fig. 1). Most tumors have the typical “triphasic” histology, consisting of primitive or blastemal cells, more differentiated or epidermal cells,
FIG. 1. Wilms’ tumor histology. Wilms’ tumor is characteristically composed of‘ primitive blastemal cells (B), epithelial cells (E), and strornal cell components (S). This “triphasic” histology is occasionally more complex with evidence of further cellular differentiation. WTI expression is found primarily within the epithelial and blastemal cell types. [Photomicrograph (hematoxylin and eosin stain) provided by Dr. Nancy Harris, Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.]
THE GENETICS OF WILMS’ TUMOR
43
along with a stromal cell component. Occasionally, regions of neural or muscle differentiation are found. One variant of Wilms’ tumor, the anaplastic cell type, is distinguished by the presence of large, grossly abnormal cells, and carries a worse clinical prognosis than the majority of tumors (Breslow et al., 1986; Douglass et al., 1986). In addition, tumors with the characteristic triphasic histology can arise outside the kidney, particularly in the retroperitoneum or elsewhere in the genitourinary tract. These extrarenal Wilms’ tumors may reflect malignant transformation in similar precursor cells in the genitourinary developmental pathway (Coppes et al., 1991). Wilms’ tumor can arise within a setting of premalignant renal lesions. Persistent metanephric blastema, so-called nodular renal blastema or nephrogenic rests, is seen in a significant number of kidneys harboring Wilms’ tumors, and in virtually all bilateral cases. These lesions may point to a genetic susceptibility that predisposes to tumor formation (Bove and McAdams, 1976). The treatment of Wilms’ tumor has advanced dramatically since the initial report by Wilms in 1899, when it was uniformly fatal (D’Angio et al., 1989; National Wilms’ Tumor Study Committee, 1991; Grundy et al., 1989). Currently, cure rates of 90% are reported by the National Wilms’ Tumor Study Group, involving multimodality treatment. Most early-stage tumors are treated by surgical resection of the affected kidney, exploration of the inferior vena cava, which can be involved with tumor cells, lymph node dissection, and examination of the contralateral kidney for any evidence of synchronous tumor. This is followed by chemotherapy using actinomycin D and vincristine, with radiation therapy reserved for tumors with adverse prognostic indicators. Wilms’ tumor is very sensitive to chemotherapy, and even patients with advanced metastatic disease have an excellent cure rate. Studies of long-term Wilms’ tumor survivors have shown a low incidence of secondary malignancies, consisting primarily of osteochondromas and sarcomas within the radiation field, and acute leukemias attributed to chemotherapy and radiation. Other than these treatment-associated malignancies, there is no convincing evidence that predisposition to Wilms’ tumor also confers susceptibility to other tumor types (Bryd and Levine, 1984). With current medical therapy, most children with Wilms’ tumor reach reproductive age and remain fertile. The risk of progeny similarly affected by Wilms’ tumor is observed to be low (Li et al., 1987). Ill. The Knudson Model Many of the recent advances that have led to the characterization of tumor suppressor genes and their role in carcinogenesis can be
44
DANIEL A. HABER AND DAVID E. HOUSMAN
understood within the framework laid by Knudson in studies of retinoblastoma, Wilms’ tumor, and neuroblastoma (Fig. 2) (Knudson, 1971; Knudson and Strong, 1972a,b). By using a mathematical model to analyze epidemiologic data on the incidence of these pediatric tumors, Knudson calculated the number of rate-limiting steps required for tumorigenesis. In the case of retinoblastoma, Knudson was able to compare the incidence of unilateral versus multiple tumors in patients with a positive family history of this tumor. The data fit the Poisson distribution for a single rare event, suggesting that in these predisposed individuals, only one genetic lesion was required for tumorigenesis. Knudson proposed that these individuals inherited one genetic mutation, and that one additional “genetic hit” in the target tissues led to the development of a retinoblastoma. Given the number of cells at risk for the second genetic event, the likelihood of tumor development is very high and multiple tumors are common. In contrast, sporadic tumors are exclusively unilateral, reflecting the requirement for two independent rare genetic events for tumor formation. The age of incidence of retinoblastoma also supports the Knudson model. Individuals with an inherited predisposition to tumor formation develop these tumors 1 to 2 years earlier than the sporadic cases. Furthermore, the age of onset of new tumors declines at an exponential rate in susceptible individuals, consistent with the exponential rate of differentiation of predisposed retinoblasts. On the other hand, in sporadic cases, the timing of the second genetic lesion is dependent on the variable timing of the initial mutation, thus producing a more delayed decline in the incidence of tumors over time. T h e predictions of the Knudson model in the case of retinoblastoma have been borne out by the cloning of the RBZ gene (Friend et al., 1986; Lee et al., 1987; Fung et al., 1987). This gene maps to a locus on chromosome 13q14, which had been linked to retinoblastoma formation by genetic analyses (Sparkes et al., 1983; Benedict et al., 1983; Cavenee et al., 1983, 1985; Dryja et al., 1984, 1986), and inactivation of the two alleles of RBI appear to comprise the two genetic hits predicted by Knudson (Dunn et al., 1988; Yandell et al., 1989). Wilms’ tumor shares a number of features with retinoblastoma. Five to 10%of cases are bilateral at presentation, and these tend to arise at a younger age than the unilateral tumors (Matsunaga, 1981). Knudson and Strong (1972a) were able to show that the two-hit model was also compatible with the incidence of Wilms’ tumor, but their analysis was limited by the small number of documented cases of familial Wilms’ tumor. With an estimated 8% incidence of bilateral tumors, Poisson sta-
45
THE GENETICS OF WILMS’ TUMOR
4
I*
3
G
FIG. 2. Schematic representation of Knudson model in Wilms’ tumor. T h e model proposed by Knudson and Strong (l972a) predicts that bilateral Wilms’ tumors result from a genetic predisposition. An initial mutation is present in the germline of the child, either as a result of parental transmission o r a de iiouo germline event. Two genetic events are rate limiting in tumorigenesis, the second event typically consisting of the loss of the wild-type allele in somatic tissues. T h e probability of a second somatic event is high in children with genetic susceptibility to Wilms’ tumor, resulting in bilateral tumors and an earlier age of onset. T h e somatic loss of the wild-type allele can occur by diverse mechanisms (chromosome recombination, nondisjunction events, as well as more subtle deletions). In Wilms’ tumors showing allelic losses, the maternal gene appears to be preferentially lost. Of note, the two Wilms’ tumor loci that have been mapped are both on the short arm of chromosome 11, allowing a single chromosomal event to inactivate both of these loci.
46
DANIEL A. HABER A N D DAVID E. HOUSMAN
tistics would predict a 30% incidence of familial cases, rather than the observed 1-2% incidence (Cochran and Froggatt, 1967; Knudson and Strong, 1972a). These observations imply that the majority of bilateral tumors may result from de novo germline events or that the penetrance of the inherited lesion may be variable. The second possibility is less likely, given the high penetrance of Wilms’ tumor in patients with congenital syndromes such as WAGR (see below). An important component of the Knudson hypothesis, as it is now interpreted, is that inactivation of one allele of a tumor suppressor gene is phenotypically silent, and abnormal growth results only following loss of the second allele (Knudson, 1985). This appears to be the case in retinoblastoma: individuals with a germline RBI mutation who do not develop a tumor during the years in which they are at risk have no detectable ocular abnormalities as adults. In contrast, patients with genetic susceptibility to Wilms’ tumor often show nephroblastosis, preneoplastic kidney lesions, even if they do not develop Wilms’ tumor (Bove and McAdams, 1976; Beckwith et al., 1990). These observations suggest that a heterozygous germline mutation is capable of inducing an abnormality in developmental growth. Whether such an initial genetic lesion can enhance the probability of an additional genetic event is unknown. The Knudson model is based on the statistics of “hit kinetics,”and therefore measures only the number of events that are rate limiting in tumor formation. Genetic events that are necessary for tumor formation but have a higher frequency than the rate-limiting steps, or are dependent on these earlier events, will not be detected in this analysis (see Haber and Housman, 1991). In the case of Wilms’ tumor, a number of genetic loci have been implicated in tumor formation, and how these loci interact with each other remains to be elucidated. IV. Genetic Loci Associated with Wilms’ Tumor
The Knudson model, as exemplified by retinoblastoma, suggests that the same locus may be,inactivated in the germline of susceptible individuals and in the somatic tissues from which a tumor arises (Knudson, 1985). Indeed, the study of both germline and tumor material, using karyotype analysis, genetic mapping with molecular markers, as well as clinical observations on patients with congenital abnormalities, led to the identification of the key genetic loci involved in Wilms’ tumorigenesis. Currently there is evidence supporting three distinct loci for Wilms’ tumor, two on the short arm of chromosome 11, and one still unidentified.
THE GENETICS OF WlLMS’ TUMOR
47
A. CHROMOSOME 1lp13 A seminal contribution to understanding the genetics of Wilms’ tumor was made by Miller and co-workers in 1964, who noted the association between Wilms’ tumor and aniridia. Aniridia, malformation or absence of the iris, occurs in 1 in 70,000 children, while Wilms’ tumor arises in 1 in 10,000 children. Despite the rarity of these two conditions, aniridia is detected in 1 in 70 children with Wilms’ tumors, and 1 in 3 children with aniridia develop such tumors. These observations were the first to imply a physical linkage between two genes responsible for two distinct phenotypes, so-called “contiguous gene syndromes” (see Table I). In addition, Wilms’ tumors arising in the context of aniridia are frequently bilateral and develop at an earlier age than sporadic tumors. Based on the Knudson model, these individuals could thus be suspected of carrying a heterozygous germline deletion, affecting both the aniridia and Wilms’ tumor genes. In the development of the eye, a hemizygous state appears sufficient to confer the aniridia phenotype, whereas in the kidney a second mutation may be necessary for the development of Wilms’ tumor. Rare individuals with Wilms’ tumor have been found to have a number of congenital abnormalities in addition to aniridia. These patients have a number of developmental abnormalities of the genitourinary tract, ranging from common conditions such as hypospadias and TABLE I CHARACTERISTICS OF Two CONGENTIAL SYNDROMES ASSOCIATED WITH WILMS’ TUMOR^ Characteristic
WAGR syndrome
Chromosomal locus Wilms’ tumor incidence Associated features
llp13 >50% Aniridia Genitourinary defects Mental retardation
~
Beckwith-Wiedemann syndrome 1 lp15
I. 11. 111. IV.
V. VI.
VII. VIII.
Introduction Histology and Clinical Considerations T h e Knudson Model Genetic Loci Associated with Wilms’ Tumor A. Chromosome 1 lp13 €3. Chromosome 1 l p l 5 C . Familial Wilms’ Tumor Isolation of the W T l Gene at 1 1p 13 WT1: Characterization of a Novel Tumor Suppressor Gene A. Gene Structure and Alternative Splicing B. Normal Tissue Expression of’WT1 C. WTI Mutations in the Germline and in Wilms’ Tumors Functional Studies and Animal Models Conclusions References
I. Introduction The isolation of the WTI gene involved in the genesis of Wilms’ tumor has provided a new molecular tool to understand the normal and abnormal development of the kidney and related tissues. Wilms’ tumor is pediatric kidney cancer, which arises in 1 in 10,000 children. It can present in both a common sporadic and a rare hereditary form, along with various congenital abnormalities. The existence of both gross chromosomal abnormalities as well as more subtle molecular deletions has led to the genetic characterization of a number of loci involved in the development of Wilms’ tumor. Within one of these loci, band 13 on the short arm of chromosome 11, we have recently isolated a gene, WTI, which is specifically inactivated in Wilms’ tumors. In this article we discuss the complex genetics of Wilms’ tumor, and the initial studies characterizing the role of the WTI gene product in tumorigenesis.
41 ADVANCES IN CANCER RESEARCH, VOL. 5Y
Copyright 0 1992 by Academic Press, Inc. All rights of reproduction in any form resemed.
42
DANIEL A. HABER AND DAVID E. HOUSMAN
II. Histology and Clinical Considerations Wilms’ tumor constitutes some 10% of all pediatric cancer, and is the most common intraabdominal solid tumor in children. The peak incidence is between 3 and 4 years of age, with most children presenting with a palpable abdominal mass. Some 5-10% of patients with Wilms’ tumor have bilateral cancers, and these children tend to present between 2 and 3 years of age (Matsunaga, 1981). Rarely, children with Wilms’ tumor will show evidence of genetic malformations and chromosomal abnormalities (see below). T h e malignant transformation in Wilms’ tumor is thought to originate in cells of the metanephric blastema (Bennington and Beckwith, 1975). This fetal structure is thought to give rise to the genitourinary system, and Wilms’ tumors are characterized by their histologic diversity (see Fig. 1). Most tumors have the typical “triphasic” histology, consisting of primitive or blastemal cells, more differentiated or epidermal cells,
FIG. 1. Wilms’ tumor histology. Wilms’ tumor is characteristically composed of‘ primitive blastemal cells (B), epithelial cells (E), and strornal cell components (S). This “triphasic” histology is occasionally more complex with evidence of further cellular differentiation. WTI expression is found primarily within the epithelial and blastemal cell types. [Photomicrograph (hematoxylin and eosin stain) provided by Dr. Nancy Harris, Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.]
THE GENETICS OF WILMS’ TUMOR
43
along with a stromal cell component. Occasionally, regions of neural or muscle differentiation are found. One variant of Wilms’ tumor, the anaplastic cell type, is distinguished by the presence of large, grossly abnormal cells, and carries a worse clinical prognosis than the majority of tumors (Breslow et al., 1986; Douglass et al., 1986). In addition, tumors with the characteristic triphasic histology can arise outside the kidney, particularly in the retroperitoneum or elsewhere in the genitourinary tract. These extrarenal Wilms’ tumors may reflect malignant transformation in similar precursor cells in the genitourinary developmental pathway (Coppes et al., 1991). Wilms’ tumor can arise within a setting of premalignant renal lesions. Persistent metanephric blastema, so-called nodular renal blastema or nephrogenic rests, is seen in a significant number of kidneys harboring Wilms’ tumors, and in virtually all bilateral cases. These lesions may point to a genetic susceptibility that predisposes to tumor formation (Bove and McAdams, 1976). The treatment of Wilms’ tumor has advanced dramatically since the initial report by Wilms in 1899, when it was uniformly fatal (D’Angio et al., 1989; National Wilms’ Tumor Study Committee, 1991; Grundy et al., 1989). Currently, cure rates of 90% are reported by the National Wilms’ Tumor Study Group, involving multimodality treatment. Most early-stage tumors are treated by surgical resection of the affected kidney, exploration of the inferior vena cava, which can be involved with tumor cells, lymph node dissection, and examination of the contralateral kidney for any evidence of synchronous tumor. This is followed by chemotherapy using actinomycin D and vincristine, with radiation therapy reserved for tumors with adverse prognostic indicators. Wilms’ tumor is very sensitive to chemotherapy, and even patients with advanced metastatic disease have an excellent cure rate. Studies of long-term Wilms’ tumor survivors have shown a low incidence of secondary malignancies, consisting primarily of osteochondromas and sarcomas within the radiation field, and acute leukemias attributed to chemotherapy and radiation. Other than these treatment-associated malignancies, there is no convincing evidence that predisposition to Wilms’ tumor also confers susceptibility to other tumor types (Bryd and Levine, 1984). With current medical therapy, most children with Wilms’ tumor reach reproductive age and remain fertile. The risk of progeny similarly affected by Wilms’ tumor is observed to be low (Li et al., 1987). Ill. The Knudson Model Many of the recent advances that have led to the characterization of tumor suppressor genes and their role in carcinogenesis can be
44
DANIEL A. HABER AND DAVID E. HOUSMAN
understood within the framework laid by Knudson in studies of retinoblastoma, Wilms’ tumor, and neuroblastoma (Fig. 2) (Knudson, 1971; Knudson and Strong, 1972a,b). By using a mathematical model to analyze epidemiologic data on the incidence of these pediatric tumors, Knudson calculated the number of rate-limiting steps required for tumorigenesis. In the case of retinoblastoma, Knudson was able to compare the incidence of unilateral versus multiple tumors in patients with a positive family history of this tumor. The data fit the Poisson distribution for a single rare event, suggesting that in these predisposed individuals, only one genetic lesion was required for tumorigenesis. Knudson proposed that these individuals inherited one genetic mutation, and that one additional “genetic hit” in the target tissues led to the development of a retinoblastoma. Given the number of cells at risk for the second genetic event, the likelihood of tumor development is very high and multiple tumors are common. In contrast, sporadic tumors are exclusively unilateral, reflecting the requirement for two independent rare genetic events for tumor formation. The age of incidence of retinoblastoma also supports the Knudson model. Individuals with an inherited predisposition to tumor formation develop these tumors 1 to 2 years earlier than the sporadic cases. Furthermore, the age of onset of new tumors declines at an exponential rate in susceptible individuals, consistent with the exponential rate of differentiation of predisposed retinoblasts. On the other hand, in sporadic cases, the timing of the second genetic lesion is dependent on the variable timing of the initial mutation, thus producing a more delayed decline in the incidence of tumors over time. T h e predictions of the Knudson model in the case of retinoblastoma have been borne out by the cloning of the RBZ gene (Friend et al., 1986; Lee et al., 1987; Fung et al., 1987). This gene maps to a locus on chromosome 13q14, which had been linked to retinoblastoma formation by genetic analyses (Sparkes et al., 1983; Benedict et al., 1983; Cavenee et al., 1983, 1985; Dryja et al., 1984, 1986), and inactivation of the two alleles of RBI appear to comprise the two genetic hits predicted by Knudson (Dunn et al., 1988; Yandell et al., 1989). Wilms’ tumor shares a number of features with retinoblastoma. Five to 10%of cases are bilateral at presentation, and these tend to arise at a younger age than the unilateral tumors (Matsunaga, 1981). Knudson and Strong (1972a) were able to show that the two-hit model was also compatible with the incidence of Wilms’ tumor, but their analysis was limited by the small number of documented cases of familial Wilms’ tumor. With an estimated 8% incidence of bilateral tumors, Poisson sta-
45
THE GENETICS OF WILMS’ TUMOR
4
I*
3
G
FIG. 2. Schematic representation of Knudson model in Wilms’ tumor. T h e model proposed by Knudson and Strong (l972a) predicts that bilateral Wilms’ tumors result from a genetic predisposition. An initial mutation is present in the germline of the child, either as a result of parental transmission o r a de iiouo germline event. Two genetic events are rate limiting in tumorigenesis, the second event typically consisting of the loss of the wild-type allele in somatic tissues. T h e probability of a second somatic event is high in children with genetic susceptibility to Wilms’ tumor, resulting in bilateral tumors and an earlier age of onset. T h e somatic loss of the wild-type allele can occur by diverse mechanisms (chromosome recombination, nondisjunction events, as well as more subtle deletions). In Wilms’ tumors showing allelic losses, the maternal gene appears to be preferentially lost. Of note, the two Wilms’ tumor loci that have been mapped are both on the short arm of chromosome 11, allowing a single chromosomal event to inactivate both of these loci.
46
DANIEL A. HABER A N D DAVID E. HOUSMAN
tistics would predict a 30% incidence of familial cases, rather than the observed 1-2% incidence (Cochran and Froggatt, 1967; Knudson and Strong, 1972a). These observations imply that the majority of bilateral tumors may result from de novo germline events or that the penetrance of the inherited lesion may be variable. The second possibility is less likely, given the high penetrance of Wilms’ tumor in patients with congenital syndromes such as WAGR (see below). An important component of the Knudson hypothesis, as it is now interpreted, is that inactivation of one allele of a tumor suppressor gene is phenotypically silent, and abnormal growth results only following loss of the second allele (Knudson, 1985). This appears to be the case in retinoblastoma: individuals with a germline RBI mutation who do not develop a tumor during the years in which they are at risk have no detectable ocular abnormalities as adults. In contrast, patients with genetic susceptibility to Wilms’ tumor often show nephroblastosis, preneoplastic kidney lesions, even if they do not develop Wilms’ tumor (Bove and McAdams, 1976; Beckwith et al., 1990). These observations suggest that a heterozygous germline mutation is capable of inducing an abnormality in developmental growth. Whether such an initial genetic lesion can enhance the probability of an additional genetic event is unknown. The Knudson model is based on the statistics of “hit kinetics,”and therefore measures only the number of events that are rate limiting in tumor formation. Genetic events that are necessary for tumor formation but have a higher frequency than the rate-limiting steps, or are dependent on these earlier events, will not be detected in this analysis (see Haber and Housman, 1991). In the case of Wilms’ tumor, a number of genetic loci have been implicated in tumor formation, and how these loci interact with each other remains to be elucidated. IV. Genetic Loci Associated with Wilms’ Tumor
The Knudson model, as exemplified by retinoblastoma, suggests that the same locus may be,inactivated in the germline of susceptible individuals and in the somatic tissues from which a tumor arises (Knudson, 1985). Indeed, the study of both germline and tumor material, using karyotype analysis, genetic mapping with molecular markers, as well as clinical observations on patients with congenital abnormalities, led to the identification of the key genetic loci involved in Wilms’ tumorigenesis. Currently there is evidence supporting three distinct loci for Wilms’ tumor, two on the short arm of chromosome 11, and one still unidentified.
THE GENETICS OF WlLMS’ TUMOR
47
A. CHROMOSOME 1lp13 A seminal contribution to understanding the genetics of Wilms’ tumor was made by Miller and co-workers in 1964, who noted the association between Wilms’ tumor and aniridia. Aniridia, malformation or absence of the iris, occurs in 1 in 70,000 children, while Wilms’ tumor arises in 1 in 10,000 children. Despite the rarity of these two conditions, aniridia is detected in 1 in 70 children with Wilms’ tumors, and 1 in 3 children with aniridia develop such tumors. These observations were the first to imply a physical linkage between two genes responsible for two distinct phenotypes, so-called “contiguous gene syndromes” (see Table I). In addition, Wilms’ tumors arising in the context of aniridia are frequently bilateral and develop at an earlier age than sporadic tumors. Based on the Knudson model, these individuals could thus be suspected of carrying a heterozygous germline deletion, affecting both the aniridia and Wilms’ tumor genes. In the development of the eye, a hemizygous state appears sufficient to confer the aniridia phenotype, whereas in the kidney a second mutation may be necessary for the development of Wilms’ tumor. Rare individuals with Wilms’ tumor have been found to have a number of congenital abnormalities in addition to aniridia. These patients have a number of developmental abnormalities of the genitourinary tract, ranging from common conditions such as hypospadias and TABLE I CHARACTERISTICS OF Two CONGENTIAL SYNDROMES ASSOCIATED WITH WILMS’ TUMOR^ Characteristic
WAGR syndrome
Chromosomal locus Wilms’ tumor incidence Associated features
llp13 >50% Aniridia Genitourinary defects Mental retardation
~
Beckwith-Wiedemann syndrome 1 lp15
