Abstract
Abstract
Lynch syndrome (LS) is the leading cause of hereditary colorectal cancer (CRC). Germline mutations in DNA mismatch-repair (MMR) genes (MLH1, PMS2, MSH2, and MSH6) are known to cause LS in the heterozygous state. Biallelic mutations in these genes cause mismatch repair cancer syndrome (MMRCS), a very rare childhood cancer syndrome that predisposes to CRC among other cancer types. In this study, we aimed to characterize the mutational landscape of LS in a large CRC cohort (n=1,207) from a population with high rates of consanguinity. The overall contribution of germline mutations in LS gene was comparable to that observed in outbred populations (26/1207). Remarkably, however, we also observed the unusual homozygous occurrence of a founder PMS2 mutation. The homozygous individual presented with massive adenomatous polyposis of the colon at age 8 years, and mutation analysis of multiple polyps revealed the occurrence of multiple independent somatic APC mutations. Our study highlights a previously unrecognized role of LS genes in triggering APC-driven tumors, a phenomenon facilitated by consanguinity.
Citation Format: Abdul K. Siraj, Sandeep K. Parvathareddy, Rong Bu, Tariq Masoodi, Khadija Alobaisi, Maha Alrasheed, Saeeda O. Ahmed, Zeeshan Qadri, Padmanaban Annaiyappanaidu, Allianah Benito, Dionne R. Rala, Fowzan Al-Kuraya, Khawla S. Al-Kuraya. The study of Lynch syndrome in a special population reveals a strong founder effect and an unusual mutational mechanism in familial adenomatous polyposis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3534.