Etiology: Genetics and Molecular Biology

Wilms tumor is an embryonal malignancy of the kidney. Most cases are sporadic, although 1-2% of patients have a familial predisposition to Wilms tumor. Familial cases of Wilms tumor are inherited in an autosomal dominant manner with variable penetrance; they are associated with an earlier age at diagnosis and increased frequency of bilateral disease. Models of Wilms tumor development propose that a genetic mutation predisposes to nephrogenic rests. These are benign foci of embryonal kidney cells that persist abnormally into postnatal life in approximately 1% of newborn kidneys and usually regress or differentiate by early childhood. The nephrogenic rests that persist may sustain additional mutations and transform into Wilms tumor. Nephrogenic rests may be intralobar, as in Wilms tumor aniridia genitourinary abnormalities and mental retardation (WAGR) and Denys-Drash syndrome, or perilobar and often multiple, as in Beckwith-Wiedemann syndrome (BWS).

Wilms tumor is genetically heterogeneous (Table 493-2). Familial Wilms tumors have been linked to FWT1 gene at chromosome 17q and FWT2 gene at chromosome 19q13. However, some families carry neither of these mutations, suggesting that additional Wilms tumor loci exist.

Table 493-2 SYNDROMES ASSOCIATED WITH WILMS TUMOR

So far the best characterized Wilms tumor gene is WT1, located at 11p13. The WT1 gene encodes a zinc finger transcription factor that is critical to normal development of the kidneys and gonads. WAGR is caused by deletion at chromosome 11p13 that includes both PAX6 and WT1 loci. Aniridia arises from the deletion of PAX6 gene that lies telomeric to the WT1 gene. Individuals with WAGR are diagnosed with Wilms tumor at an earlier age and generally have a favorable histology; their tumors respond well to treatment but are associated with increased risk of end-stage renal disease (ESRD) as they approach adulthood. Individuals with intragenic WT1 germline mutation display the same Wilms tumor predisposition and range of genitourinary anomalies as patients with WAGR. Individuals with specific WT1 missense mutations additionally have early-onset renal failure (Denys-Drash syndrome). WT1 is homozygously inactivated in 10-20% of Wilms tumors, by either somatic alterations or a combination of germline and somatic WT1 alterations.

WT2 is a localized to a cluster of imprinted genes at 11p15. Altered expression of one or more of these genes due to duplication or loss of imprinting is observed in BWS. Loss of heterozygosity (LOH) or loss of imprinting (LOI) at 11p15 is observed in approximately 70% of Wilms tumors. Candidate genes in this region include IGF2, H19, CDKN1/p57kip, and KCNQ1OT1/LIT1. Uniparental isodisomy of 11p15 and hypermethylation of H19 are associated with development of Wilms tumor only, whereas alterations in KCNQ1OT1 are associated with other tumors, macrosomia, and abdominal wall defects in addition to Wilms tumor. Identification of inherited microdeletions within the H19/IGF2 imprinting control region (ICR) in BWS and BWS/Wilms tumor further strengthen the association between aberrant expressions of IGF2 and Wilms tumor development. WTX at X11.1 has now been reported to be somatically mutated in 20-30% of Wilms tumors. CTNNB1, located at 3p22.1, encodes β-catenin and is also somatically mutated in about 15% of Wilms tumors. The WNT signaling pathway seems to be commonly involved in Wilms tumorigenesis. In addition to these genes, loci at 1p, 7p, 16q, and 17p (p53 tumor suppressor gene) are also believed to harbor genes involved in the biology of Wilms tumor.

Epidemiology

The incidence of Wilms tumor is approximately 8 cases/million children <15 yr of age with about 500 new cases in North America per year. It accounts for nearly 6% of pediatric malignancies and is the second most common malignant abdominal tumor in childhood. Although peak incidence is between 2 and 5 yr of age, Wilms tumor has also been encountered in neonates, adolescents, and adults. It can arise in one or both kidneys. The incidence of bilateral Wilms tumors is 7%, and individuals with horseshoe kidney are at twice the risk for development of Wilms tumor as the general population. Wilms tumor may be associated with hemihypertrophy, aniridia, genitourinary anomalies, and a variety of rare syndromes (see Table 493-2), including BWS and Denys Drash syndrome.

Clinical Presentation

The most common initial clinical presentation for Wilms tumor is the incidental discovery of an asymptomatic abdominal mass