Book Summary:
The most common known molecular defect in Wilms tumor (WT) is loss of imprinting (LOI) of the insulin-like growth factor II gene (IGF2), which involves activation of the normally silent maternal allele and hypermethylation of a differentially methylated region (DMR) upstream of the H19 gene. Hypermethylation impairs binding of the insulator protein CTCF allowing activation of IGF2 by an enhancer shared between IGF2 and H19. LOH of 16q22.1 is found in 12% of WT, and 16q22.1 harbors CTCF, raising the possibility that reduced CTCF could lead to LOI of IGF2 in some cases. LOH of 16q was found in five of 40 WT, of which one tumor also showed LOH of 11p15. Each of the four tumors showed LOI of IGF2 (P = 0.040). Including data published previously, 6 of 6 tumors with 16q LOH (without LOH of 11p) showed LOI of IGF2 (P = 0.015). Thus, a genetic (16q LOH) and epigenetic (LOI of IGF2) alteration in WT are linked, the first such association described. Haploinsufficiency of CTCF may be the basis of this association, as CTCF expression in tumors with 16q LOH was 48% that of tumors without LOH. The only known Wilms tumor suppressor gene is WT1, deletions or mutations of which account for 10–20% of WT. A second locus (WT2) is believed to map to 11p15, a region lost frequently in WT that harbors a domain of imprinted genes. Maternal specific LOH of 11p15 suggests that WT2 is an imprinted tumor suppressor gene. Hypothetically, imprinted silencing could act as one of the two ‘hits’ necessary to inactivate WT2 expression, with loss of heterozygosity (LOH) acting as the second ‘hit.’ Tumors were assessed for relative expression of SLC22A18 using quantitative Real-Time PCR, followed by allele specific expression analysis. One allele of SLC22A18 was inactivated due to imprinting in the matched normal tissue of one of seven (14%) informative WT with 11p15 LOH. Results suggest that this gene does not frequently fill the role of putative imprinted tumor-suppressor gene, but may be affected by epigenetic silencing of one allele, independent of LOH, in both tumor types tested. |