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Researchers identify non-BRCA genes associated with breast, ovarian cancers

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August 28, 2018

Whole-exome sequencing confirmed well-known breast and ovarian cancer gene associations and identified MSH6 and ATM as possible moderate-risk predisposition genes, according to published findings.

“These results ... have the potential to serve as the foundation for future epidemiologic, clinical or functional studies of breast cancer or ovarian cancer and to inform comprehensive genetic testing and clinical practice,” Hsiao-Mei Lu, PhD, vice president of bioinformatics and computational biology at Ambry Genetics Inc., and colleagues wrote.

Approximately 5% to 20% of all breast or ovarian cancers are related to genetic abnormalities. BRCA1 and BRCA2 account for at least 25% of familial risk.

However, several large case-control studies have identified more genes susceptible to these cancers.

Only 10% to 24% of patients referred for risk assessment with genetic testing for breast or ovarian cancer harbored known pathogenic variants identified by multigene panel testing.

Research on cancer risks associated with less well-characterized genes is needed due to increased use of multigene panel testing with moderate-risk genes.

To determine whether additional cancer genes not currently included in most multigene panel tests contribute to risk, researchers performed large-scale whole-exome sequencing among 11,416 patients with breast cancer, ovarian cancer or both referred for genetic testing between 2014 and 2015, and reference controls (n = 3,988) who underwent genetic testing for noncancer conditions.

Researchers also conducted case-control analyses using the Genome Aggregation Database.

Among 9,639 patients with breast cancer (1.3% men), 41.1% had early-onset disease, 13.7% had bilateral or multiple breast cancers, and 6.6% had additional cancer primaries.

Men received diagnosis at an older age than women (mean age, 61.8 years vs. 48.6 years).

Among 2,015 women with ovarian cancer, 21.7% received a diagnosis at age 45 years or younger.

A total 84.6% of patients with breast cancer and 81.4% with ovarian cancer reported a family history of cancer.

Further, 18% of all patients provided information on BRCA1/BRCA2 testing prior to whole-exome sequencing, 98.7% of whom had negative results. Thus, researchers noted this population was enriched for non-BRCA carriers.

Overall, researchers identified pathogenic variants among four non-BRCA genes associated with increased risk for breast cancer: ATM (OR = 2.97; 95% CI, 1.67-5.68); CHEK2 (OR = 2.19; 95% CI, 1.4-3.56); PALB2 (OR = 5.53; 95% CI, 2.24-17.65); and MSH6 (OR = 2.59; 95% CI, 1.35-5.44), which is a Lynch syndrome susceptibility gene that had not previously been known to be associated with breast cancer .

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Researchers confirmed these four genes were associated with similar or higher risks in the Genome Aggregation Database.

Researchers also identified pathogenic variants among four genes assocaited with increased risk for ovarian cancer: MSH6 (OR = 4.16; 95% CI, 1.95-9.47) and ATM (OR = 2.85; 95% CI, 1.3-6.32) — both of which are recent discoveries — as well as TP53 (OR = 18.5; 95% CI, 2.56-808.1) and RAD51C (OR = not estimable; false discovery rate-corrected P = .004).

Researchers noted the OR for RAD51C could not be estimated because of the lack of pathogenic variants among controls; however, RAD51C was associated with high ovarian cancer risk in the comparison set from the Genome Aggregation Database.

Also, MSH6 appeared associated with early-onset ovarian cancers.

Analyses did not identify increased risk associated with MRN complex genes MRE11A, RAD50 and NBN, or with CDKN2A. Also, the findings did not support previously reported breast cancer associations with the following ovarian cancer susceptibility genes: BRIP1, RAD51C and RAD51D; or mismatch repair genes MSH2 and PMS2.

Study limitations included missing information on personal disease history of the controls, possible underestimation of risk for less-studied genes and lack of hormone receptor status for all patients.

“Our findings in a large sample of patients referred for genetic testing confirmed several known or suspected associations with breast cancer or ovarian cancer and implicate new roles for genes involved in genomic maintenance,” researchers wrote.

The use of non-BRCA genetic testing for breast and ovarian cancer is increasing for certain genotypes, Stephanie L. Greville-Heygate, MSc, of University of Southampton in the U.K., and colleagues wrote in a related editorial.

“Overall, the early identification of individuals with genetic variants assocaited with hereditary breast or ovarian cancer has the potential to achieve health benefits through cascade predictive genetic testing; primary risk reduction, including screening, chemoprophylaxis and risk-reducing surgery; and, increasingly, through active cancer management,” they wrote.

It remains important to understand that cancer risks conferred by constitutional genotype are modifiable by polygenic factors and environmental exposures.

“As such, genotype should be viewed as an important tool for cancer risk stratification that may not be fully representative of the entire complement of risk factors that and individuals may possess,” they added. – by Melinda Stevens

Disclosures: All study authors report employment with Ambry Genetics Inc. at the time of the study. The editorial authors report no relevant financial disclosures.

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