Abstract 431: CYP26C1 gene is highly methylated and correlated with chemoradiation therapy in esophageal squamous cell carcinoma

Abstract

Abstract Background: Systemic chemo- and chemoradiation- therapy is widely accepted in esophageal squamous cell carcinoma (ESCC) patients. However resistance to these therapies remaining pretty high and multicentric occurrence of ESCC often can see after treatment. Multiple studies have shown that promoter methylation of tumor suppressor genes underlie esophageal carcinogenesis. But, we still do not know that epigenetic changes after chemoradiation therapy (CRT) in ESCC. Our aim is to identify how change DNA methylation in tumor site (T) but also adjacent normal site (ADJ) before/after CRT. Methods: Tumor and adjacent normal biopsy specimens were obtained before/after treatment from 34 patients (124 samples) enrolled in a uniform CRT protocol. Genomewide DNA methylation analysis was performed using 12 non-treated test samples (T and matched ADJ: 6 each) by methylated CpG island amplification and microarray (MCAM) method (4x44K, Agilent custom array), and selected candidate genes that were highly methylated in T than ADJ. We next analyzed one of the candidate genes CYP26C1 (cytochrome P450, family 26, subfamily C, polypeptide 1) DNA methylation using 112 validation samples by quantitative bisulfate pyrosequencing. Results: CYP26C1 was selected by unsupervised hierarchical clustering after MCAM in test samples. CYP26C1 DNA methylation was significantly high in T than ADJ in both test and validation samples (p<0.04, T: 60.7±7.6, ADJ: 44.5±11.5). However some ADJ also showed high methylation in validation samples. Moreover, CYP26C1 methylation in both T and ADJ were significantly depressed after CRT (T: p<0.01 (45.1±18.3 to 31.6±14.9), ADJ: p<0.0001 (43.8±10.3 to 30.5±13.8)). Conclusions: CYP26C1 has a CpG island in promoter area and was highly methylated in T of ESCC patients. And, some ADJ showed high CYP26C1 methylation, suggesting possibility of multicentric occurs of ESCC. Moreover, CYP26C1 methylation depress after CRT both T and ADJ, suggesting potential clinical application of CRT sensitive biomarker. Citation Format: Yoshiyuki Watanabe, Ritsuko Oikawa, Yoshihito Yoshida, Hiroyuki Yamamoto, Fumio Itoh. CYP26C1 gene is highly methylated and correlated with chemoradiation therapy in esophageal squamous cell carcinoma. [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 431. doi:10.1158/1538-7445.AM2014-431