Improving breast cancer risk assessment in Israel through genomics​

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Sapir Shemesh1, Hagai Levi2, Rinat Bernstein Molho3,4, Eitan Friedman4,5, Ron Shamir2, Ran Elkon1

 

1Department of Human Molecular Genetics and Biochemistry, Gray Faculty of Medical & Health Sciences, Tel Aviv University

2The Blavatnik School of Computer Science and Artificial Intelligence, Tel Aviv University

3The Suzanne Levy-Gertner Oncogenetics Unit, Danek Gertner Institute of Human Genetics, Sheba Medical Center, Ramat Gan, Israel;

4Gray Faculty of Medical & Health Sciences, Tel-Aviv University, Tel-Aviv, Israel

5The Meirav High-Risk Clinic, Sheba Medical Center, Ramat Gan, Israel

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I will present two projects aimed at enhancing the assessment of genetic predisposition to breast cancer (BC) in Israel.

 

The first project focuses on sporadic BC. Previous studies demonstrated that polygenic risk score (PRS) models—constructed based on GWAS data—can identify women at significantly elevated BC risk. However, these PRS models are based on GWASs performed primarily in women of European (EUR) ancestry, and the generalizability of EUR-based PRS models to other populations remains a major open question. In our study, we evaluated the performance of EUR-based BC PRS models in Israeli women. Using an Israeli cohort of 1,437 cases and 724 controls from the Breast Cancer Association Consortium, we optimized a PRS model specifically for Israeli Ashkenazi Jewish (AJ) women. We showed that women in the top 10% of the PRS distribution had fourfold higher odds of developing BC compared to those in the bottom 10%. These findings demonstrate that PRS models based on EUR GWASs can identify AJ women at markedly elevated BC risk, paving the way for precision-medicine approaches to mammography screening in Israel.

The second project focuses on women carrying pathogenic variants (PVs) in BRCA1. Such women are at substantially elevated BC risk. However, the age at BC diagnosis varies widely, even among carriers of the same PV in BRCA1. Despite extensive efforts over the past two decades, the identification of genetic modifiers in BRCA1 carriers remains limited. We applied—for the first time in this context—a large-scale whole-exome sequencing analysis to a cohort of 321 Israeli women carrying the BRCA1 185delAG AJ founder PV. Notably, we found that carrying additional putatively damaging missense variants in genes involved in innate immunity was significantly associated with earlier BC onset. These preliminary findings highlight a potential role for innate immune pathways as modifiers of BRCA1 penetrance.