Abstract
Abstract Aims: Radiation therapy is used to treat half of all cancer patients, but response to radiation therapy varies widely among patients. Studies aimed at predicting individual responsiveness to preoperative radiation therapy (CRT) are urgently needed, especially considering the risks associated with poorly responsive patients. Methods: This study adopted a three-step process to select radiosensitive candidates of methylation genes. In the first step, a genome-wide creening of methylation genes was performed using Infinium humanMethylation450K Beadchip according to the correlation with istopathologic tumor regression grade (TRG) of 45 patients with locally advanced rectal cancer (LARC). In the second step, methylation status of selected sites was analyzed with pyrosequencing in the other 98 LARC patients. Finally, candidate gene identified by second screening was verified by biological utility assessment using cell viability assays of transfected colorectal cancer (CRC) cells. Results: Genome-wide creening identified that hypermethylation of 7 CpG sites (DZIP cg24107021, DZIP cg26886381, ZEB1 cg04430381, DKK3 cg041006961, STL cg00991794, KLHL34 cg01828474, ARHGAP6 cg07828380) were associated with preoperative CRT responses. Patients carrying hypermethylated KLHL34 cg14232291 were confirmed to show radiosensitivity by pyrosequencing in additional patients. Knockdown of KLHL34 significantly reduced colony formation and increased cytotoxicity in LoVo cells. It increased radiation induced caspase-3 activity and sub G1 population.Conclusions: In this study, we showed that methylation status of KLHL34 cg14232291 may be a predictive marker of radiosensitivity to preoperative CRT, although further validation is needed in large cohorts. Citation Format: Yejin Ha. Epigenetic regulation of KLHL34 may be predictive of pathologic response to preoperative chemoradiotherapy in rectal cancer patients. [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 2295. doi:10.1158/1538-7445.AM2014-2295
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