Diversified risk.

Top Line: What genetic variants are associated with an increased risk of breast cancer?

The Study: BRCA1 and BRCA2 right? The widespread availability and decreasing cost of genetic sequencing has expanded our understanding of breast cancer association genes. These two important studies help inform an updated approach to breast cancer susceptibility testing. The first study from the BCAC evaluated truncating variants and rare missense variants in 34 genes in >65k breast cancer patients and >50k controls. The second study from CARRIERS consortium evaluated 28 genes in >30k breast cancer patients and >30k controls. First of all, which genes were most strongly associated with an increased risk of breast cancer? In the larger BCAC study, 5 genes were strongly associated with breast cancer risk (ATM, BRCA1, BRCA2, CHEK2, and PALB2) while 7 other genes (so 12 genes in total) were at least modestly associated with increased risk. Second, which genes had the highest absolute risk of breast cancer? In both studies, BRCA1, BRCA2, and PALB2 were associated with the highest absolute risk of breast cancer. Finally, were any genes associated with certain breast cancer subtypes? In both studies, ATM and CHEK2 were associated with increased risk of ER+ tumors--both in situ and invasive. BARD1, BRCA1, BRCA2, PALB2, and RAD51C/D were associated with ER- tumors.

TBL: These large case-control studies expand our understanding of breast cancer susceptibility genes. | Dorling and Hu, N Engl J Med 2021

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