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Etiology
Epidemiology
Malignant renal tumours comprise 6% of all childhood cancers, with Wilms' tumour (WT) being the most frequent type (90%). The overall annual incidence is 9.1 per million children in Europe increasing by 0.7% per year, and 8.1 in North America. Over 77% of WTs are diagnosed in children before 5 years of age and 15% before the age of 1 year. The male to female ratio is 0.9. The incidence rates show two peaks, at ages 1 and 3 years. This pattern is especially marked in females. The median age at diagnosis is 3 years for females compared with 2 years for males. WT in adults is rare but well known. Children with unilateral tumours are older than cases with bilateral ones.
The majority of WT are solitary lesions, but approximately 12% of children develop multifocal tumors within a single kidney and almost 7% have bilateral involvement at diagnosis or later on.
Incidence rates around the world are higher in North America and Europe compared to Asia. Epidemiological studies suggest that ethnicity affects the incidence rates more than geographical region of residence. These observations, in addition to inconsistent results from case-control studies, suggest that environmental factors play a marginal role in the aetiology of this tumour.
Cancer genetics
Genetic predisposition to WT has long been recognised in patients with aniridia and the WAGR syndrome. Today we know that the genetic bases and molecular biology of WT is very heterogeneous and more complex than anticipated. All underlying syndromes can be divided into overgrowth syndromes and others. Besides gene mutations loss of heterozygosity (LOH) and loss of imprinting (LOI) can be found in tumour cells. In the development of WT different genes and mutations are involved making it difficult to explain pathogenesis by a simple "two-hit" hypothesis. LOH affects most often the genes 1p, 7p, 11p, 16q and 22q. Additional tumor suppressor or tumor-progressive genes may lie on chromosomes 16q and 1p as evidenced by LOH for these regions in 17% and 11% of Wilms' tumors, respectively. Patients classified by tumor-specific loss of these loci had significantly worse relapse-free and overall survival rates.
The genetics of the overgrowth syndromes are complex and carry a risk of WT in the order of 10%. Like the Beckwith-Wiedemann syndrome (BWS) they arise from mutations or abnormalities of imprinting in genes in the 11p15.5 region with different constitutional epigenotypes between BWS and hemihypertrophy. If the analysis of the methylation status of several genes in this region will predict an individual risk of developing a WT is an open question.
The WAGR syndrome is caused by a complete deletion of one copy of the WT gene, WT1 and the adjacent aniridia gene, PAX6 on chromosome 11p13. In patients with aniridia this information helps to identify those patients, who are on risk for developing WT, by screening them for the combined deletion of WT1 and PAX6. WT1 is also involved in the Denys Drash syndrome (early onset nephrotic syndrome, Wilms' tumour, and ambiguous genitalia) caused by a germ line point mutation. A similiar constitutional WT1 mutation underlies the Frasier syndrome (nephropathy and gonadal tumors. It is of interest that in only 5% of Wilms' tumours a constitutional and in further 10% a sporadic WT1 mutation can be found. In those with germ line mutations bilateral WTs are more frequent. The WT1 protein functions as a transcription factor that is clearly critical for normal kidney development. There is a close correlation between WT1 mutations and the histology of stromal predominat tumors with rhabdomyomatous features.
In familial WTs, about 1 % of patients, there is usually no associated congenital abnormality or predisposition to other tumour types. Genetic linkage studies in different families have localised one gene for familial WT, FWT1, to chromosome 17q and another, FWT2, to 19q. Further FWT genes are waiting for identification, for there are other families known clearly unlinked to any currently identified Wilms' tumour locus.