Abstract P3-13-07: A comprehensive germline genetic landscape in young Jewish & Arab women with breast cancer

Abstract Background: After decades of research on Ashkenazi Jewish (AJ) founder mutations in BRCA1 and BRCA2 (BRCA), there is still little known about genetics in non-AJ and Arab breast cancer populations in Israel and non-BRCA pathogenic variants (PV) in the total population. We used multigene panel testing (MGPT) to characterize the spectrum and prevalence of PV in cancer susceptibility genes in various Jewish and Arab demographic subgroups. Methods: A population-based cohort of women diagnosed with breast cancer before the age of 46 in a defined geographical area in Northern Israel was recruited as part of the BCINIS study and underwent MGPT. Probability matrices of proportion of PV by gene, and by ethnic sub-group (AJs, Sephardi Jews of North African origin, Sephardi Jews of other Eastern origins, Arabs), age-sub-group (35 and under, 36-45) and first-degree family history of breast, ovary or pancreatic cancer were calculated. Results: Overall, 1650 women were tested, including 1012 Jewish, 530 Arab and 108 non-Jewish/non-Arab women. We detected 375 PV among 363 women (22.7%): 212 in AJ (33.4% of AJs), 61 in Sephardi Jews (14.2% of Sephardi), and 69 in Arabs (13.0% of Arab). Only 162 of the PV (43.2%) were the BRCA AJ founders, another 39 BRCA PV (10.4%) were reported previously, while 15 BRCA PV (4.0%) are likely private. The remaining non-BRCA PV (42.4%) were distributed across 18 genes, with findings predominantly in CHEK2, MUTYH, ATM, BLM, ERCC3, PALB2, and FANCA. The prevalence of PV varied significantly across the ancestral subsets, from 95.5% probability in AJ women diagnosed before age 36 and with first degree family history to only 9.3% in Arab women diagnosed at age 36-45 and without family history. Conclusions: In this comprehensive, population-based, cohort of women with young onset breast cancer, the presence of PV in more than 15 genes is compelling and informs a necessarily broader approach to genetic testing and counseling. Citation Format: Gad Rennert, Bita Nehoray, Flavio Lejbkowicz, Sara Dishon, Shiri Kalet, Joseph Herzog, Thomas Slavin, Danielle Castillo, Kevin Tsang, Sharon Sand, Hedy S Rennert, Jeffrey Weitzel. A comprehensive germline genetic landscape in young Jewish & Arab women with breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-13-07.