Abstract 4921: Next-generation sequencing as a potential tool in the diagnostics of APC mosaicism in FAP patient

Abstract

Abstract Familial adenomatous polyposis (FAP) is a hereditary disease characterized by the development of multiple adenomatous polyps ranging from hundreds to thousands in the large intestine, and extra-colonic tumors. Patients are predisposed to colorectal cancer that accounts for ∼1% of newly diagnosed colorectal cancer cases. Most of FAP cases result from germline mutations in the tumor suppressor gene APC (adenomatous polyposis coli), but some cases are caused by germline mutations in MUTYH, POLD1, or POLE. The rate of mutation detection depends on the methods used for genetic testing and the genes analyzed in the patients. Although sequence analysis of APC by the Sanger method is routinely performed for genetic testing, there remain cases whose mutations are not detected by the analysis. Next-generation sequencing (NGS) has enabled us to analyze the comprehensive human genome, improving the chance of identifying disease causative variants. In this study, we conducted whole-genome sequencing of a sporadic adenomatous polyposis patient in which we did not find any pathogenic APC mutations by the conventional Sanger sequencing. As a result, whole-genome sequencing and subsequent amplicon-based targeted sequencing identified a mosaic mutation of c.3175G>T, p.E1059X in approximately 12% of his peripheral leucocytes. Additional deep sequencing of his buccal mucosa, hair follicles, non-cancerous mucosa of the stomach and colon disclosed that these tissues harbored the APC mutation at different frequencies. Our data suggest that genetic testing by NGS facilitates the identification of genetic mosaicism responsible for hereditary diseases. NGS will improve genetic diagnosis of hereditary diseases whose mutations have been overlooked by conventional direct sequencing. Citation Format: Kiyoshi Yamaguchi, Mitsuhiro Komura, Rui Yamaguchi, Seiya Imoto, Eigo Shimizu, Shinichi Kasuya, Tetsuo Shibuya, Seira Hatakeyama, Norihiko Takahashi, Tsuneo Ikenoue, Keisuke Hata, Giichiro Tsurita, Masaru Shinozaki, Yutaka Suzuki, Sumio Sugano, Satoru Miyano, Yoichi Furukawa. Next-generation sequencing as a potential tool in the diagnostics of APC mosaicism in FAP patient. [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 4921. doi:10.1158/1538-7445.AM2015-4921