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Triple-Negative Breast Cancer Risk Linked to Germline Variants in Several Cancer Genes

NEW YORK (GenomeWeb) – Germline alterations affecting a handful of cancer-associated genes appear to dial up the risk of breast cancer, new research suggests, particularly triple-negative breast cancers (TNBC) that do not express receptors for estrogen, progesterone, or the human epidermal growth factor.

"This study is the first to establish which genes are associated with high lifetime risks of triple-negative breast cancer," corresponding author Fergus Couch, a laboratory medicine, pathology, and genetics researcher at the Mayo Clinic in Rochester, Minnesota, said in a statement.

Couch and his colleagues searched for suspicious germline mutations in panel sequence data generated for almost 8,800 TNBC cases assessed at the Ambry Genetics clinical testing laboratory, focusing on 21 genes implicated in cancer risk and another 2,148 individuals with TNBC who received panel sequencing across 17 cancer-related genes through a Triple-Negative Breast Cancer Consortium (TNBCC) study.

From these data, the team tracked down risky germline mutations in the BARD1, BRCA1/2, PALB2, and RAD51D genes that were linked to breast cancer — and with an especially high risk of TNBC — in individuals with Caucasian ancestry. Alterations in the BRIP1, RAD51C, and TP53 genes had apparent ties to TNBC as well, albeit at more moderate risk levels. Similar patterns were found in women with African-American ancestry, though the number of participants in that cohort was much smaller. The work appeared online today in the Journal of the National Cancer Institute.

"While previous studies have found genetic variants in BARD1, BRIP1, PALB2, and RAD51C [in] 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," Couch said.

The analysis, which was sponsored by Ambry Genetics and supported with additional grants from the National Institutes of Health, focused on 10,901 TNBC cases. The researchers had data for 8,753 individuals assessed for potential germline mutations with a 21-gene panel sequencing at the Ambry clinical testing lab in California between March 2012 and June 2016, along with 2,148 more TNBC cases from the TNBCC that were tested with a 17-gene panel.

After identifying pathogenic and likely pathogenic variants in these genes, the team looked for those that were over-represented in TNBCC compared to controls from the Cancer Genome Atlas project, a non-Finnish European population study, or the Exome Aggregation Consortium database.

The team tracked down pathogenic germline variants in one or more of the cancer-related genes in 12 percent of the study participants overall, and pathogenic changes involving BRCA1 or BRCA2 were particularly common.

A set of high risk variants in BARD1, BRCA1/2, PALB2, and RAD51D were associated with a more than five-fold increase in TNBC in Caucasian individuals, the researchers reported, and a 20 percent jump in breast cancer risk overall. They saw more than double the risk of TNBC when pathogenic or likely pathogenic changes in the BRIP1, RAD51C, and TP53 genes occurred in the germline.

In Caucasian women with pathogenic variants in BRCA1, for example, the team estimated that the absolute risk of TNBC is about 18 percent, while the absolute risk of TNBC surpassed 20 percent in the African-American women when pathogenic variants were present in one of several genes.

"The results suggest that all TNBC patients should undergo multigene panel testing, regardless of age at diagnosis or family history of cancer, for improved cancer risk assessment and because of the ongoing development of targeted therapeutic approaches for TNBC patients with mutations in predisposition genes," Couch and his co-authors concluded.