Abstract 3549: Low frequency of germline mutations in POLE and POLD1 proofreading domains in Middle Eastern colorectal cancers

Abstract Colorectal cancer (CRC) is one of the main causes of cancer related morbidity and mortality. Only ~ 5% of all CRCs occur as a result of mutations in well-defined CRC predisposing genes. The underlying causes in genetically unexplained CRC cases from Middle Eastern region are still unknown. We performed Capture sequencing and Sanger sequencing to screen the proofreading domains of DNA Polymerase Epsilon (POLE) and DNA Polymerase Delta 1 (POLD1) genes to find out the genetic causes in over 1100 CRC cases from Middle Eastern region. In our cohort, five mutations (0.44%) were identified in 1135 CRC cases, four in POLE gene (0.35%, 4/1135) and one (0.1%, 1/1135) in POLD1 gene. These mutations have been infrequently reported in Western populations. Furthermore, low expression of POLE was noted in 38.9% (417/1071) of cases and showed significant association with lymph node involvement (p=0.0184) and grade 3 tumors (p=0.0139). Whereas, low expression of POLD1 was observed in 51.9% (555/1069) of cases and was significantly associated with adenocarcinoma histology (p=0.0164), larger tumor size (T3 and T4 tumors; p=0.0012) and stage III tumors (p=0.0341). Our findings revealed that there was a low frequency of mutations in POLE and POLD1 proofreading region in CRC cases and established that the mutations in the proofreading domain of these two genes were a rare cause of CRC in Middle Eastern region. It is feasible to screen multiple cancer related genes in CRC patients from Middle Eastern region using multigene panels including POLE and POLD1. Citation Format: Rong Bu, Abdul K. Siraj, Kaleem Iqbal, Sandeep K. Parvathareddy, Tariq Masoodi, Nabil Siraj, Nabil Siraj, Maha Al-Rasheed, Sarah Siraj, Yan Kong, Saeeda O. Ahmed, Khadija A.S. Al-Obaisi, Ingrid G. Victoria, Khawla S. Al-Kuraya. Low frequency of germline mutations in POLE and POLD1 proofreading domains in Middle Eastern colorectal cancers [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 3549.