In a study reported in JAMA Oncology, researchers from the Breast Cancer Association Consortium found that pathogenic germline variants in nine breast cancer susceptibility genes were associated with different breast cancer subtypes, although most were also associated with triple-negative disease.
Study Details
The case-control analysis of the BRIDGES study involved 42,680 patients and 46,387 controls sampled independent of family history from 38 large-scale population- or hospital-based studies performed between 1991 and 2016. All participants were of European or East Asian ethnicity. Sequencing and analysis were performed between 2016 and 2021. Associations between tumor subtypes and protein-truncating variants and likely pathogenic missense variants in ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53 were assessed.
The results of this case-control study suggest that variants in the nine breast cancer risk genes differ substantially in their associated pathology but are generally associated with triple-negative and/or high-grade disease. Knowing the age and tumor subtype distributions associated with individual breast cancer genes can potentially aid guidelines for gene panel testing, risk prediction, and variant classification and guide targeted screening strategies.— Breast Cancer Association Consortium researchers
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Key Findings
Overall, the distribution of intrinsic subtypes by gene exhibited wide heterogeneity.
Variants in RAD51C (odds ratio [OR] = 6.19, 95% confidence interval [CI] = 3.17–12.12), RAD51D (OR = 6.19, 95% CI = 2.99–12.79), and BARD1 (OR = 10.05, 95% CI = 5.27–19.19) were primarily associated with triple-negative disease. RAD51D variants were also significantly associated with hormone receptor–positive, HER2-negative high-grade tumors (OR = 4.82).
CHEK2 variants were associated with all subtypes (ORs = 2.21–3.17) except for triple-negative disease.
ATM variants were most strongly associated with hormone receptor–positive, HER2-negative high-grade tumors (OR = 4.99, 95% CI = 3.68–6.76).
PALB2 variants were associated with all subtypes, with the highest odds ratios for hormone receptor–positive, HER2-negative high-grade tumors (9.43, 95% CI = 6.24–14.25) and triple-negative disease (8.05, 95% CI = 5.17–12.53).
BRCA1 variants were associated with increased risk of all subtypes, with the highest odds ratio for triple-negative disease (55.32, 95% CI = 40.51–75.55); odds ratios for other subtypes ranged from 2.27 to 9.85. BRCA2 variants were most strongly associated with hormone receptor–positive, HER2-negative high-grade disease (OR = 11.53, 95% CI = 8.92–14.90) and triple-negative tumors (OR = 10.07, 95% CI = 7.61–13.32).
TP53 variants were most strongly associated with hormone receptor–negative, HER2-positive and hormone receptor–positive, HER2-positive disease, with no association with triple-negative disease being observed.
Overall, tumors in carriers of pathogenic variants were of higher grade. Decreases in odds ratios with increasing age were observed for BRCA1, BRCA2, and CHEK2. Together, the nine genes were associated with 14.4% of all tumors in women age ≤ 40 years and < 4% of tumors in those aged > 60 years, and were associated with 27.3% of all triple-negative tumors in those aged ≤ 40 years.
The investigators concluded, “The results of this case-control study suggest that variants in the nine breast cancer risk genes differ substantially in their associated pathology but are generally associated with triple-negative and/or high-grade disease. Knowing the age and tumor subtype distributions associated with individual breast cancer genes can potentially aid guidelines for gene panel testing, risk prediction, and variant classification and guide targeted screening strategies.”
Nasim Mavaddat, MBBS, MPhil, PhD, of the Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, is the corresponding author for the JAMA Oncology article.
Disclosure: The study was supported by the European Union Horizon 2020 research and innovation program, Wellcome Trust, and others. For full disclosures of the study authors, visit jamanetwork.com.
