Abstract 963: Epigenetic silencing of cancer-specific methylation may converge on therapeutic targets on human cancers

(Background) We have identified numerous candidate tumor suppressor genes (TSGs) which are inactivated by cancer-specific CpG island methylation. We reviewed differential patterns of cancer-specific methylation in esophageal squamous cell carcinoma, gastric adenocarcinoma, and colorectal adenocarcinoma. (Matherials and Methods) A modified pharmacological unmasking microarray in combination with tissue expression patterns identified novel cancer-specific methylation in each organ site, and we tabulated methylation frequency for each type of cancer. (Results) (1) In esophageal squamous cell carcinoma, we discovered cancer-specific methylation for NEFH (84%), NMDAR2B (78%), DCC (74%), cyclin A1 (60%), CRBP1 (52%), HOPX (50%), trypsinogen-4 (50%), and PGP9.5 (42%). (2) In gastric adenocarcinoma, we validated cancer-specific methylation for HOPX (87%), Reprimo (78%), PGP9.5 (70%), NMDAR2B (70%), and RIZ1 (40%). (3) In colorectal adenocarcinoma, we identified cancer-specific methylation for Beta 4 GalT1 (82%), Oncostatin MR (80%), DFNA5 (65%), LIFR (65%), and HOPX (52%). (4) From our estimates, about 300 genes were frequently methylated specifically in cancer tissues, and among them, and around 70% of these genes were upstream or downstream of the p53 pathway (NMDAR2AB, DCC, cyclin A1, PGP9.5, HOPX, Reprimo, DFNA5). Apoptotic pathways other than those in the p53 pathway, including death receptor signaling was also observed. Another 30% of methylated genes antagonize unique oncogenic pathways in individual cancers. Either NEFH or HOPX was involved in inactivation of pAkt through an unknown mechanism or PTEN induction in ESCC. RIZ1 uniquely inactivated in gastric cancer, is an inhibitor of the IGF receptor pathway. Oncostatin M R or LIFR in CRC are inhibitors of pStat3. All inactivated TSG candidates were demonstrated to be robustly reactivated by de-methylating agents. (Conclusion) In GI cancers, numerous genes involved in p53 activation are commonly suppressed in expression, and epigenetic reversion of p53 activity may be beneficial for killing cancer cells more efficiently. Moreover, unique oncogenic inhibitors will need to be developed for specific targets in similar but related pathways for varied organ sites. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 963. doi:1538-7445.AM2012-963