Abstract 1439: Genetic profiling of colitis-associated cancer indicates de novo carcinogenesis and the impact of chronic inflammation

Background: Chronic inflammation is one of the major causes of carcinogenesis. Ulcerative colitis (UC) and Crohn’s disease (CD) increase the risk of colitis-associated cancer (CAC) development, and its biological and pathological characters are also distinct. However, the genetic mechanism of how chronic inflammation leads to CACs is still unclear. Methods: We obtained frozen tumor tissues from 21 CAC patients and performed exome or whole-genome sequencing of the matched tumor-normal samples. We enumerated recurrently mutated genes and selected 43 genes among them for target capture. We then performed targeted resequencing of 84 FFPE specimens from CAC tissues. Totally, we made genomic profiles of 105 CACs. Results: The most frequently mutated gene was TP53, whose mutation was found in 70 of 105 samples (67%), which is more prevalent in CACs than common colorectal cancers (CRCs). Somatic mutations of APC and KRAS were less prevalent (17 and 13 samples, respectively). Genes in the Wnt signaling pathway (APC, FBXW7, TCF7L2, and RNF43) were mutated in 31 samples, whereas those in the TGFβ pathway (TGFBR2, ACVR1B, SMAD2, SMAD4, LTBP4) were mutated in 25 samples. Mutational signature of CACs shows some differences from common CRCs. Conclusion: Our results confirmed genetic differences for cancer development between CACs and common CRCs. Frequent TP53 mutations and less frequent APC mutations are consistent with the idea of “de novo” carcinogenesis than adenoma-carcinoma sequence. The association between the mutations and clinical information are also discussed. Citation Format: Masashi Fujita, Nagahide Matsubara, Kazuhiro Maejima, Tomoki Yamano, Ikuo Matsuda, Seiichi Hirota, Hiroki Ikeuchi, Naohiro Tomita, Hidewaki Nakagawa. Genetic profiling of colitis-associated cancer indicates de novo carcinogenesis and the impact of chronic inflammation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1439. doi:10.1158/1538-7445.AM2017-1439