August 07, 2018
3 min read

Researchers identify pathogenic variants linked to triple-negative breast cancer risk

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Photo of Fergus Couch 2018
Fergus J. Couch

Multigene hereditary cancer panel testing can identify women at increased risk for triple-negative breast cancer based on mutations in BARD1, BRCA1, BRCA2, PALB2 and RAD51D, according to study findings.

“This study is the first to establish which genes are associated with high lifetime risks of triple-negative breast cancer,” Fergus J. Couch, PhD, Zbigniew and Anna M. Scheller professor of medical research, and chair of the division of experimental pathology at Mayo Clinic in Rochester, Minnesota, said in a press release. “While previous studies have found genetic variants in BARD1, BRIP1, PALB2 and RAD51C triple-negative breast cancer patients, the current study shows this in more detail, and identifies new specific and strong associations between the susceptibility genes RAD51D and BARD1, and triple-negative breast cancer risk.”

Treatment options are limited for triple-negative breast cancer, an aggressive form of breast cancer that constitutes 15% of all cases among white patients and 35% of all cases among black patients.

“It is also associated with a high risk of recurrence and a poor 5-year survival rate,” Couch said in the release.

Germline genetic testing with hereditary cancer gene panels have been used to identify women at increased risk for breast cancer. However, women at increased risk for triple-negative breast cancer have not been identified due to a lack of established predisposition genes apart from BRCA.

Researchers tested for 21 genes — BRCA1, BRCA2, PALB2, BARD1, BRIP1, NF1, MSH2, MSH6, PMS2, CDKN2A, RAD51C, RAD51D, RAD50, NBN, MRE11A, ATM, CHEK2, TP53, PTEN, STK11, CDH1 — among 8,753 patients (mean age at diagnosis, 49.8 years) with triple-negative breast cancer who underwent clinical germline cancer panel testing at a clinical laboratory between March 2012 and June 2016.

Investigators also tested for 17 predisposition genes — BRCA1, BRCA2, PALB2, BARD1, BRIP1, RAD51C, RAD51D, RAD50, NBN, MRE11A, XRCC2, ATM, CHEK2, TP53, PTEN, STK11, CDH1 — among 2,148 patients (mean age at diagnosis, 50.8 years) from a study conducted by the Triple-Negative Breast Cancer Consortium, which served as a reference control group.

Among patients from the clinical cohort, 62.8% were white and 14.5% were black, whereas 97.5% of patients among the consortium cohort were white.

Researchers observed pathogenic variants in all 21 genes among 14.4% of patients of any race or ethnicity in the clinical cohort — this included a 14% rate among whites, and a 14.6% rate among blacks. Among the consortium cohort, 14.5% had pathogenic variants in 17 genes.

The most commonly mutated non-BRCA1/2 genes among both cohorts was PALB2 (1% to 1.6%) and BARD1 (0.5% to 0.7%).


Researchers observed an association between high risk — based on an OR greater than 5 — for triple-negative breast cancer and BRCA2 pathogenic variants among white patients in the clinical cohort (OR = 5.42; 95% CI, 4.13-7.05) and the consortium cohort (OR = 6.33; 95% CI, 4.48-8.92).

Researchers also observed increased risk associated with pathogenic variants in PALB2 (OR = 14.41; 95% CI, 9.27-22.60), BARD1 (OR = 5.92; 95% CI, 3.36-10.27) and RAD51D (OR = 6.97; 95% CI, 2.60-18.66) among the clinical cohort.

A moderately increased risk — defined by an OR more than 2 — for triple-negative breast cancer occurred for pathogenic variants in BRIP1, RAD51C and TP53 genes.

“Results from this study further characterize the role of these genes in triple-negative breast cancer and also introduce a novel association between RAD51D and risk for triple-negative breast cancer,” the researchers wrote.

Trends appeared similar across white and black populations.

Pathogenic variants in triple-negative breast cancer genes occurred among 12.7% of 1,271 black patients, including 3.7% in non-BRCA genes.

An exploratory case control analysis that included black patients from the clinical cohort and the Genome Aggregation Database suggested that pathogenic variants in BRCA1, BRCA2, BARD1 and PALB2 could be associated with high or moderate risk for triple-negative breast cancer.

Researchers noted National Comprehensive Cancer Network guidelines — which recommend BRCA1 and BRCA2 testing for patients diagnosed with triple-negative breast cancer at 60 years of age or younger, or who meet criteria based on personal and family cancer history — may need to be revised.

“As most of these variants are considered clinically actionable, [our] findings suggest that testing criteria for triple-negative breast cancer patients should be expanded to include testing of all breast cancer predisposition genes regardless of age of diagnosis or family history of cancer,” the researchers wrote. – by Melinda Stevens

Disclosures: The authors report no relevant financial disclosures.