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Nine Genes Implicated in More Than a Quarter of All TNBC in Young European and East Asian Women
Pathogenic variants in 9 genes are associated with more than a quarter (27.3%) of all triple-negative breast cancer tumors in women 40 and younger, according to a case-control analysis of almost 90,000 participants from the BRIDGES study. The genes identified were ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53; all except CHEK2 were associated with high-grade disease.
“Women carrying variants in these genes may be offered enhanced screening, including by magnetic resonance imaging, risk-reducing surgery, chemoprevention, and genetic counselling; knowledge of germline gene variants also affects treatment,” wrote lead author Nasim Mavaddat, MBBS, PhD, and co-authors.
BRIDGES was a multicenter, international study of women between the ages of 18 and 79, 42,680 of whom were patients, while 46 387 were controls. The subjects, who were all of European or East Asian ethnicity, were sampled independently of family history from 38 studies which took place between 1991 and 2016. The sequencing and analysis took place between 2016 and 2021.
RAD51C, RAD51D, and BARD1 variants were associated mainly with triple-negative disease (OR, 6.19 [95% CI, 3.17-12.12]; OR, 6.19 [95% CI, 2.99-12.79]; and OR, 10.05 [95% CI, 5.27-19.19], respectively). Likewise, BRCA2 and PALB2 variants were also associated with triple-negative disease. While variants in BRCA1 were associated with increased risk of all subtypes, the ORs were highest for triple-negative disease (OR, 55.32; 95% CI, 40.51-75.55). The strongest association for ATM variants was with the hormone receptor (HR)+ ERBB2− high-grade subtype (OR, 4.99; 95% CI, 3.68-6.76). On the other hand, TP53 variants were most strongly associated with HR+ ERBB2+ and HR– ERBB2+ forms of breast cancer.
Source:
Breast Cancer Association Consortium, Mavaddat N, Dorling L, Carvalho S, et al. Pathology of Tumors Associated With Pathogenic Germline Variants in 9 Breast Cancer Susceptibility Genes. JAMA Oncol. Published online January 27, 2022. doi: 10.1001/jamaoncol.2021.6744.
