Abstract 2792: Pericentromeric repeats undergo genome-wide DNA hypomethylation associated with older colorectal cancer patients without mutant p53 and are target for a reverse epigenetic switching

Among the somatic epigenetic changes hallmark of cancer, DNA hypomethylation has undergone a renaissance recently. Its significance in cancer is supported by the fact that global hypomethylation has been found in every tumor type studied to date, both benign and malignant. Global hypomethylation primarily reflects the somatic demethylation of DNA repetitive elements, which account for a large fraction of the human genome. Global DNA hypomethylation have been proposed to predispose to decondensation of normally compacted DNA, which in turn could promote chromosomal instability due to homologous recombination involving DNA repeats. Thus, hypomethylation of DNA may play a significant role in carcinogenesis by increasing genetic instability to favor tumor progression. In a previous study, we analyzed over 150 random chromosomal locations in a series of colon and gastric carcinomas. The main finding was that epigenetic damage in cancer cells, especially hypomethylation, increased with patient age and appeared to precede genomic damage. These findings led to a “wear and tear” model for cancer development: hypomethylation of sensitive pericentromeric repetitive elements accumulate irremediably during aging eventually leading to errors in recombination and chromosome replication, thus originating genomic instability in the road to cancer. One of the loci exhibiting a wide degree of demethylation, occurring in a significant proportion of both colorectal (26%) and gastric (20%) tumors, corresponded to SST1, a non-coding pericentromeric DNA repetitive element. Bisulfite sequencing showed that demethylation of SST1 elements also occurs in breast (15%) and ovarian (20%) tumors thus showing universal implication in cancer. Colon cancer cases with hypomethylation of SST1 exhibited higher levels of genomic damage (GDF) than cases with normal methylation levels. In addition, demethylation of SST1 significantly associated with higher GDF in cancers with wild type than mutant p53. Also, DNA hypomethylation increased more with the age of colon cancer patients whose tumors harbored wild type P53 than in those cancers with mutant p53. Chromatin immunoprecipitation experiments (ChIP) showed an association between SST1 hypomethylation and histone H3 lysine 27 (H3K27) trimethylation, an epigenetic repressive mark of facultative heterochromatin. We have termed this phenomenon, reversed epigenetic switching, which seems to be sequence-specific, since our preliminary analysis revealed that hypomethylation of other repetitive DNA does not associate to significant changes in H3K27 methylation. These findings suggest that severe demethylation of SST1 pericentromeric elements may be a marker for a revese epigenetic swicth that associates to changes in chromatin structure ultimately affecting chromosomal integrity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2792. doi:10.1158/1538-7445.AM2011-2792