March 2026: Shemesh & Elkon: New study identifies immune pathways as key modifiers of breast cancer risk and explains why breast cancer appears earlier in some BRCA1 carriers than others

BRCA1 is the major risk gene for breast cancer (BC). women who carry pathogenic variants (mutations) in this gene have a substantially elevated lifetime risk of developing BC. To mitigate this risk, BRCA1 carriers are often advised to undergo risk-reducing surgeries, including the removal of the breasts and ovaries. However, these interventions are invasive, irreversible, and associated with profound life-altering consequences. Notably, the age of BC onset varies considerably among BRCA1 carriers, and current understanding of genetic risk modifiers in this population remains limited.

Sapir Shemesh, an Edmond J. Safra PhD Fellow, together with her advisor Prof. Rani Elkon, Edmond J. Safra member (Medical & Health Sciences), led a collaborative study with clinicians from Sheba Medical Center to address this gap. The team performed whole‑exome sequencing of a large cohort of Ashkenazi Jewish (AJ) BRCA1 carriers whose age at breast cancer onset ranged widely, from 26 to 75 years (mean age at diagnosis: 41.5). Their analysis revealed that additional and potentially damaging variants in genes involved in immune system activation are significantly associated with an earlier onset of BC.

These findings highlight a previously underappreciated role for immune pathways as modifiers of BC risk in BRCA1 carriers and support the development of more refined, personalized risk prediction models for women carrying BRCA1 mutations. This is of particular importance in Israel, where Ashkenazi Jews have the highest population prevalence of BRCA1 carriers worldwide (~1% of individuals).

The study was published in the Journal of Medical Genetics and has already attracted attention from online medical news outlets.

Read more here.