• Epigenetic changes in cancer include alterations in methylation of CpG-rich regions—especially in promoters—with associated altered gene expression; loss of imprinting of genes that normally show parent-of-origin-specific expression; and chromatin alterations, associated with methylation and acetylation of histones.
• IGF2 and H19 are reciprocally regulated imprinted genes in the WT2 locus on chromosome 11p15. IGF2 is expressed on the paternal chromosome (“paternally expressed” or “maternally imprinted”), while H19, which encodes a spliced but untranslated RNA, is maternally expressed.
• Hypermethylation of the H19 promoter is associated with loss of expression of H19 and expression of IGF2. LOH of the 11p15 locus is seen in up to 43% of untreated Wilms’ tumors and studies have shown preferential loss of the maternal allele
• In addition, more than 60% of the remaining tumors show loss of expression of H19 associated with biallelic hypermethylation. Consistent with reciprocal H19/IGF2 control, tumors with loss of expression of H19 show IGF2 LOI with overexpression.
• This is seen more commonly with tumors in older children, tumors in perilobar nephrogenic restlike tumors, and in Wilms’ tumors associated with Beckwith-Wiedemann syndrome. IGF2 LOI is not seen in tumors linked to the WT1 locus on 11p15. In addition, 11p13 LOI is seen less commonly among Wilms tumors in Asian children.
• Other genetic changes that are commonly seen in Wilms’ tumors are mutations in WT1 on 11p15, and mutations in the Beta-catenin gene CTNNB1 and WTX, which is part of the beta-catenin degradation complex. CTNNB1 and WTX mutations are mutually exclusive.
