Loss of methylation at chromosome 11p15.5 is common in human adult tumors

Abstract

Chromosome 11p15 deletion is frequent in human tumors, suggesting the presence of at least one tumor suppressor gene within this region. While mutation analyses of local genes revealed only rare mutations, we have previously described a mechanism, gain of imprinting, that leads to loss of expression of genes located on the maternal 11p15 chromosome in human hepatocarcinomas. Loss of expression was often associated with loss of maternal-speci®c methylation at the KvDMR1 locus. Here, we show that loss of the maternal KvDMR1 methylation is common, ranging from 30 to 50%, to a variety of adult neoplasms, including liver, breast, cervical and gastric carcinomas. We found that other 11p15.5 loci were concomitantly hypomethylated, indicating that loss of KvDMR1 methylation occurred in the context of a common mechanism a ecting the methylation of a large 11p15 subchromosomal domain. These epigenetic abnormalities were not detected in any normal somatic tissue. Therefore, it seems possible that, contrary to the repression of promoter activity caused by hypermethylation, loss of gene expression at 11p15.5 may result from the activation, by hypomethylation, of one or more negative regulatory elements.

Monoallelic Methylation of the APC Promoter Is Altered in Normal Gastric Mucosa Associated with Neoplastic Lesions

“…The most commonly involved gene is the IGF2 gene, located on chromosome 11p15.5. Along with IGF2, other genes in the 11p15.5 locus were hypomethylated, suggesting a hypomethylation mechanism affecting a large subchromosomal domain (41). We are currently studying the methylation pattern of other genes located in the APC locus to verify this hypothesis.…”

Epigenetic analysis of HIC1, CASP8, FLIP, TSP1, DCR1, DCR2, DR4, DR5, KvDMR1, H19 and preferential 11p15.5 maternal-allele loss in von Hippel-Lindau and sporadic phaeochromocytomas

“…This suggests that in this case an epigenetic change (an 'epimutation') at KvDMR1 might promote tumourigenesis by downregulation of CDKN1C (and possibly increased IGF2 expression). KvDMR1 demethylation has also been observed in a variety of cancers, including liver, breast, cervical and gastric, but somatic CDKN1C mutations have not been reported (Scelfo et al 2002).…”

microRNA Involvement in Hepatocellular Carcinoma

“…Because of differences in risk factors, regional incidence is widely variable. It ranges from 5.5 to 14.9 per 100,000 individuals, but it may reach 100 per 100,000 in some regions of [40][41][42][43]. As it will be described below, one of the major mechanisms involved in the down-regulation of p27 and p57 is now believed to be the overexpression of the microRNAs (miRNAs) miR-221/222, which occurs in about 70% of HCCs [44][45][46].…”