Abstract 1448: Unraveling the oncogenic pathway of serrated polyposis syndrome driven by RNF43 germline mutation

Abstract Serrated polyps can arise in a sporadic or familial polyposis setting and predispose to colorectal cancer (CRC). Recently, we have identified RNF43 germline mutation in a family with Serrated Polyposis Syndrome (Yan et al, GUT 2016). The presence of second somatic hit in all serrated polyps examined from members of this family further confirmed the pathogenicity of RNF43 germline mutation. In an attempt to further delineate the global genomic alterations in these serrated polyps, so as to understand the RNF43 driven serrated neoplasia pathway for the development of colorectal cancer, we performed whole exome sequencing (WES) on two sessile serrated adenomas (SSAs) resected from an RNF43 germline mutation carrier, together with the paired blood DNA. Consistent with the results from our previous Sanger sequencing study, WES detected complete inactivation of RNF43 through a 2nd hit somatic mutation, c.461 C>T P154L, or loss of heterozygosity (LOH) in the two SSAs, respectively. We also identified 51 and 58 somatic mutations in the two SSAs, respectively. BRAFV600E mutation was the only shared mutation between the two polyps. Interestingly, each of the SSAs carried a truncating mutation in a histone-methyltransferase gene, either PRDM9 or SETD1B, respectively. Other truncating or deleterious mutations included chromatin modifiers (CHD2, CHD4, TSPYL2) or other genes with methyltransferase activity (TRMT2B, METTL12, METTL14, ECE2). In addition, we found few instances of chromosomal aberration or LOH, apart from a region of LOH at chromosome 17 encompassing RNF43 in one of the SSAs. Overall, we have revealed the genomic landscape of two sessile serrated adenomas resected from a germline RNF43 mutation carrier. The results confirmed somatic RNF43 2nd hit and BRAFV600E mutation as the key events, along with putative roles for histone methyltransferase, as well as other chromatin modifiers. These findings highlight the potentially important role of an altered chromatin in the oncogenic pathway of serrated neoplasia. Citation Format: Helen Hoi Ning Yan, Jeffrey C W Lai, Siu Lun Ho, Anthony K W Chan, Wai Yin Tsui, Annie S Y Chan, Siu Tsan Yuen, Suet Yi Leung. Unraveling the oncogenic pathway of serrated polyposis syndrome driven by RNF43 germline mutation [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 1448. doi:10.1158/1538-7445.AM2017-1448