Abstract 1381: Somatic DNA demethylation and epigenetic reprogramming of SST1 pericentromeric repeats associate with genomic damage in colorectal cancer

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Genomic instability is a driving force in tumorigenesis, but recent studies indicate that epigenetic changes may precede genetic alterations and genomic instability. Global hypomethylation has been linked to oncogene-specific activation, disruption of genomic imprinting, chromosomal alterations and increased tumor frequency in both in vitro and in vivo mouse models. DNA hypomethylation in cancer cells primarily reflects the somatic demethylation of DNA repetitive elements, which account for a large fraction of the human genome. In normal cells, DNA methylation stabilizes chromosomes by silencing non-coding DNA and transposable DNA elements. Thus, hypomethylation is particularly severe in pericentromeric heterochromatin and results in centromeric decondensation, enhancing chromosome recombination and leading to deletions, translocations, and chromosomal rearrangements. We previously proposed a “wear & tear” model linking aging and genetic instability through the gradual increase of somatic demethylation during aging and its association with genomic disruption. In this study we identified a family of SST1 pericentromeric repetitive elements frequently demethylated in human cancer. Colorectal cancers (CRC) with SST1 hypomethylation exhibited higher levels of genomic damage than those with normal levels. In addition, demethylation of SST1 significantly associated with higher genomic damage in patients with wild type but not with mutant p53. We further separated the SST1 demethylated tumors into those with moderate and those with “severe” demethylation. The first group included older patients with wild-type p53 conforming to the “wear & tear” model, where SST1 demethylation may be a marker for a driver role of demethylation for chromosomal instability. The second group preferentially included younger patients and mutant p53 whereby the causal or consequential link of demethylation with genomic instability remains to be established. Furthemore, SST1 hypomethylation associated with increased levels of histone H3 lysine 27 trimethylation (H3K27me3) and decreased H3K9me3. SST1 induced-demethylation by 5-Aza-dC led to a decrease in DNA methylation accompanied by a H3K9me3 decrease and accumulation of H3K27me3. The data suggest that when SST1 elements are demethylated, they are reprogrammed to a more relaxed and plastic heterochromatin. Chromatin Immunoprecipitation (ChIP) on CRC primary samples including formalin-fixed paraffin embedded (FFPE) tissues confirmed the shift from high levels of H3K9me3 in normal tissues with methylated SST1 to increased levels of H3K27me3 in SST1 hypomethylated tumors. These findings suggest that demethylation of SST1 elements may be a marker of an epigenetic reprogramming event, associated with changes in chromatin structure that may ultimately affect chromosomal integrity. Citation Format: Johanna Samuelsson, Gabrijela Dumbovic, Sergio Alonso, Sonia Forcales, Manuel Perucho. Somatic DNA demethylation and epigenetic reprogramming of SST1 pericentromeric repeats associate with genomic damage in colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1381. doi:10.1158/1538-7445.AM2014-1381