Abstract 3473: Comprehensive genetic screening in hereditary colorectal cancer

Abstract

Abstract High-penetrant pathogenic variants in established genes associated with hereditary colorectal cancer (CRC) explain the disease in approximately 5-6% of cases. In as much as 20%-30% of all, including sporadic CRC cases, genetic factors are thought to play a significant role. Dependent on technical as well as limitations due to interpretation challenges, the high-penetrant pathogenic variants are gathered in the exonic regions of the genes. Contributions of pathogenic variants in genes, not traditionally associated with hereditary CRC have also recently been recognized. It is crucial for the patients to get a correct molecular diagnosis that allows for adequate follow-up since the majority of the syndromes include predisposition also for tumors in other organs. A comprehensive panel including high-penetrant susceptibility genes as well as genes not generally associated with hereditary CRC was used for the analyses. Sequencing of 50 kb upstream and downstream of all genes including intronic regions were performed. All SNVs and CNVs in exons were thoroughly evaluated concerning pathogenicity and also intronic and intragenic sequences were screened for the presence of possibly pathogenic variants. In addition, cDNA were analysed to detect variants in splice-sites as well as aberrations causing other effects on mRNA level. The study included 206 patients referred to the Cancer Genetics Counselling Clinic in Gothenburg, Sweden. The spectra of pathogenic variants in well-known high-penetrance predisposition genes as well as the contribution of pathogenic variants in low-penetrant genes were determined. The contribution of pathogenic variants also in “non-CRC” genes was examined. The findings include identification of previously unreported variants and putative causative variants in unexplained patients with hereditary CRC. An attempt to identify putative genetic variants that could explain the variability in cancer risk among carriers of specific variants in high-penetrance genes was also made. Citation Format: Anna Rohlin, Frida Eiengård, Emma Mårtensson, Theofanis Zagoras, Samuel Gebre-Medhin, Margareta Nordling. Comprehensive genetic screening in hereditary colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3473.