It’s All in the Genes: Germline Variants Affect Clinical Subtypes of Breast Cancer

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Holly Magliochetti

Genetics Institute of America

Genetics Institute of America (GIA) is a national laboratory dedicated to heightening the awareness of early intervention and genetic screening to promote the longevity and quality of life outcomes.  


It’s All in the Genes:

Germline Variants Affect Clinical Subtypes of Breast Cancer

DELRAY BEACH, FL – Clinical subtypes determined by the estrogen receptor (ER), progesterone receptor (PR), and HER2 tumor markers are commonly used to determine treatment strategy and disease prognosis. “Approximately 70% of breast cancers are ER positive (ER+) tumors, including 10.0/20.0% ER+/HER+ and 50.0-60.0% ER+/HER2-, whereas 15.0% are ER negative (ER-)/HER2+ tumors and 15.0% are ER-/PR-/HER- triple-negative breast cancers (TNBC).”1 Associations between germline variant predisposition and certain clinical subtype are unclear. Previous studies have shown that “germline mutations in BARD1, BRIP1, PALB2, RAD51C, RAD51D, and TP53 have been associated with increased risks of TNBC and mutations in BARD1, BRCA1, BRIP1, RAD51C, and RAD51D are more frequent in TNBC than other subtypes of breast cancer.”1 Targeted therapies and approaches for specific germline variants make understanding these associations vital for proper patient care and improved overall survival rate.

A recent study published in the Journal of the National Cancer Institute by researchers from Mayo Clinic was designed to understand the connection between germline variants and the clinical subtype of a patient’s breast cancer. Within the over 50,000 patient study sample, germline pathogenic variants were found in “8.6% of patients with ER+/HER-, 8.9% with ER+/HER2+, 7.7% with ER-/HER2+, and 14.4% of ER-/PR-/HER2- tumors. BRCA1, BRCA2, BARD1, and PALB2 mutations were enriched in ER- and HER2- tumors; RAD51C and RAD51D mutations were enriched in ER- tumors only; TP53 mutations were enriched in HER2+ tumors, and ATM and CHEK2 mutations were enriched in both ER+ and/or HER2+ tumors.”1

Based on the data, the researchers inferred that germline variants can confer subtype specific risks for a breast cancer patient. This information, coupled with age at diagnosis, could help a physician more clearly define a treatment strategy that is individualized to the patient. Individualized care using germline genetic testing and proper risk assessment are crucial factors that must be implemented to improve overall survival rate for the different breast cancer subtypes.

  1. Hu C, Polley EC, Yadav S, et al. The Contribution of Germline Predisposition Gene Mutations to Clinical Subtypes of Invasive Breast Cancer From a Clinical Genetic Testing Cohort. J Natl Cancer Inst. 2020;112(12):1231-1241. doi:10.1093/jnci/djaa023
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