Abstract 1053: Potential utility of DNA methytlation as a biomarker for prediction of ulcerative colitis associated colitic cancer (UCAC)

Abstract

Abstract Background: Patients with Ulcerative colitis (UC) have more increased risk for the development of colorectal cancers compared with the average-risk population. Methods or strategies other than intensive colonoscopic surveillance to diagnose ulcerative colitis-associated colorectal carcinoma (UCAC) at early stage are limited. DNA methylation is deeply involved in carcinogenesis in many tumor types and its potential utility as a biomarker has been suggested. Aim: To evaluate potential utility of DNA methylation as the risk marker for UCAC, we quantified DNA methylation of inflamed rectal mucosa, neoplastic tissue and adjacent colonic mucosa of UC patients. Method: Inflamed rectal mucosa (n = 84) and normal appealing proximal mucosa (n = 10) of 84 cancer-free UC patients were examined. Neoplastic tissue (n = 33) and adjacent colonic mucosa (n = 26) from 16 UC patients with neoplasia (UCAC or DALM) were also studied. Bisulfite pyro sequencing was performed for the quantification of 45 cancer or age-related candidate panels and LINE1 repetitive element. Illumina Infinium Human Methylation 450 platform was also used to determine 470,000 CpG sites distributed across the genome. Results: Inflamed mucosa in UC was characterized as hyper methylation in candidate panels using the helical unsupervised clustering. In several panels, hyper methylation was associated with severe clinical phenotypes including steroid dependent, refractory, longstanding severe inflammation etc. (DPYS and miR-1247: p<0.05. GSTP1: p<0.01. mean of three: p<0.0001). Notably, in many panels, hyper methylation was significantly associated with longer duration of disease in cancer-free patients. Among them, some panels showed hyper methyhlation in both neoplastic and adjacent tissue compared to rectal mucosa of cancer-free cases (DPYS and N33, both p values <0.0001). Genome scale analysis revealed that UC with severe inflammation or neoplasia was characterized as hyper methylation at CpG sites rather than outside CpG sites. Gene ontology analysis demonstrated frequently methylated promoter CpG sites in these cases frequently encoded protein related to biosynthetic process (Fold enrichment: 2.07. p value using Benjamini correction: 5.69E-05). Conclusion: Hyper methylation at CpG sites of non-neoplastic colonic mucosa in UC with severe inflammation and neoplasia suggested the potential utility of DNA methytlation as a biomarker for prediction of UCAC. Moreover, enrichment of specific pathway in methylated genes suggests the possibility of targeting therapy for treating UCAC. Citation Format: Tomomitsu Tahara, Naoko Nakano, Mitsuo Nagasaka, Yoshihito Nakagawa, Tomoyuki Shibata, Naoki Ohmiya, Ichiro Hirata. Potential utility of DNA methytlation as a biomarker for prediction of ulcerative colitis associated colitic cancer (UCAC). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1053. doi:10.1158/1538-7445.AM2015-1053