Several Genetic Variants Associated With Increased TNBC Risk


A study using multigene panel testing identified several pathogenic variants associated with an increased risk of triple-negative breast cancer.

A study using multigene panel testing identified several pathogenic variants associated with an increased risk of triple-negative breast cancer (TNBC; estrogen receptor–negative, progesterone receptor–negative, and HER2-negative). These included variants in BARD1, BRCA1, BRCA2, PALB2, and RAD51D.

Current guidelines recommend testing for BRCA1/2 in certain patients. “However, recommendations for testing of other genes are not fully established because the risks of TNBC associated with mutations in cancer predisposition genes have not been established,” wrote study authors led by Hermela Shimelis, PhD, of the Mayo Clinic in Rochester, Minnesota. “Thus, a better understanding of gene-specific risks for TNBC is needed to identify the genes that should be tested in the setting of TNBC.”

The new study used a multigene panel test that included 21 genes in 8,753 TNBC patients, along with testing for 17 genes in another 2,148 patients from a TNBC Consortium cohort (TNBCC). They compared these patients with more than 26,000 control subjects from the Exome Aggregation Consortium (ExAC). The results of the analysis were published in the Journal of the National Cancer Institute.

Pathogenic variants (PVs) in BRCA1 were associated with a high risk of TNBC, which was consistent with previous research. BRCA2 PVs were also found to be associated with higher risk, with an odds ratio (OR) in the larger cohort of 5.42 (95% CI, 4.13–7.05; P < 2.2×10-16) and in the TNBCC cohort of 6.33 (95% CI, 4.48–8.92; P < 2.2×10-16).

Other genes were also associated with TNBC risk in the larger clinical cohort. PVs in PALB2 had an OR for TNBC of 14.41 (95% CI, 9.27–22.60; P < 2.2×10-16); for BARD1, the OR was 5.92 (95% CI, 3.36–10.27; P < 2.2×10-9); and for RAD51D PVs, the OR was 6.97 (95% CI, 2.60–18.66; P = 3.1×10-4). PVs in BRIP1 and RAD51C were associated with a more modest increased risk of TNBC.

These were similar in the TNBCC cohort as well, and an analysis that compared Caucasian and African-American patients saw no significant differences between the groups. In total, PVs in the moderate- and high-risk genes were seen in 12.0% of the larger cohort and in 13.2% of those in the TNBCC cohort.

“If these data are correct, what it means is that when we are considering genetic testing for a woman because she has TNBC, we should not just test for BRCA1, but include these other breast cancer genes,” said Mary B. Daly, MD, PhD, of the Fox Chase Cancer Center in Philadelphia, who was not involved with the study. She noted that many years of previous data had found similar risk for TNBC in the general population and in BRCA2 carriers, raising questions about the control population used.

“The bottom line is, this is provocative data and may raise questions about what genetic and/or epigenetic factors result in TNBC, but I would like to see it confirmed in other populations with more defined control populations,” Daly said.

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