Abstract LB-382: Identification of predisposing genes for small bowel adenocarcinoma by exome sequencing
Authors: Hänninen Ulrika A. , Katainen Riku , Tanskanen Tomas , Hamberg Jiri , Ristimäki Ari , Pukkala Eero , Taipale Minna , Mecklin Jukka-Pekka , Aavikko Mervi , Forsström Linda M. , Pitkänen Esa , Mäkinen Netta , Aaltonen Lauri A. 
Published: August 2018

Abstract
Small bowel adenocarcinoma (SBA) is a rare but aggressive cancer type with limited treatment options. Known predisposing factors include Crohn's disease, celiac disease, and hereditary syndromes such as familial adenomatous polyposis (FAP), Lynch syndrome, and Peutz-Jeghers syndrome. Here, our aim was to further characterize genetic susceptibility to SBA in a large population-based cohort and simultaneously demonstrate the ability to utilize tumor-only data to cost-effectively but reliably call germline variants.
Information on all SBAs diagnosed in Finland between the years 2003-2011 were collected utilizing the Finnish Cancer Registry that maintains a nation-wide database on all cancer cases diagnosed in Finland since 1953. From these we selected all SBAs 1) confirmed as small bowel primary tumor, 2) with available tumor material, and 3) tumor content of at least 50%. Additionally, all relevant medical records were available for all cases. Altogether 106 tumors representing all three parts of the small bowel were selected for exome sequencing. The variant calls were produced with GATK HaplotypeCaller. Germline calls were extracted from the data by filtering out somatic calls that were originally produced by e.g. filtering SNV and indel calls against whole-genome and exome samples of the GnomAD dataset (n=138,632). To focus on possible disease-causing variants, the remaining putative germline variants with allele frequency &gt;0.001 in the whole GnomAD and population-specific Finnish GnomAD set (n=1,747) were excluded. The germline origin of the observed, most prominent variants are being verified by Sanger sequencing, whenever corresponding normal DNA is available.
First, we considered variants that were truncating or predicted damaging in silico in the 106 known cancer predisposing genes according to COSMIC. Eight of the 106 genes harbored such variants in at least two patients. We detected the pathogenic germline variant in all patients known to have a hereditary cancer syndrome (MLH1/MSH6 in three Lynch syndrome and APC in two FAP cases). We also identified two patients with a BRCA2 germline variant, one truncating and the other one predicted damaging. BRCA2 might play a role in SBA, thus far germline BRCA2 variants have been observed at least in cancers of the ampullary region. Next, we widened the analysis for other candidate genes but preliminary results show no clear candidates that would be shared by several patients. We will also look more closely into genes belonging to the same signaling pathways as the known syndrome causing genes. Finally, no single gene mutated in all the patients with celiac disease (n=10) was observed nor were there clear differences in the germlines of patients with and without celiac disease. This population-based study on predisposing variants in SBAs provides new information on their molecular genetic background, possibly having an impact also on their treatment.
Citation Format: Ulrika A. Hänninen, Riku Katainen, Tomas Tanskanen, Jiri Hamberg, Ari Ristimäki, Eero Pukkala, Minna Taipale, Jukka-Pekka Mecklin, Mervi Aavikko, Linda M. Forsström, Esa Pitkänen, Netta Mäkinen, Lauri A. Aaltonen. Identification of predisposing genes for small bowel adenocarcinoma by exome sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-382.