Large Study Sheds Light on Genetic Susceptibility in Breast, Ovarian Cancer

A large study confirmed previously reported associations between several genes and breast cancer and ovarian cancer risk, while also identifying several genes that had not previously been associated with these malignancies.

In the years since the discovery of the BRCA1 and BRCA2 genes and their association with breast cancer, a number of other possibly connected genes have also emerged. “Further investigation of cancer risks associated with less well-characterized genes is imperative, particularly as multigene panel testing that includes moderate-risk genes are increasingly used in oncology practice,” wrote study authors led by Hsiao-Mei Lu, PhD, of Ambry Genetics in Aliso Viejo, California.

To further characterize the genetic landscape in this setting, the researchers used whole-exome sequencing of 11,416 patients with clinical features of breast cancer, ovarian cancer, or both, referred for genetic testing from 1,200 hospitals. These were compared with sequencing data from 3,988 control patients who were referred for genetic testing for other reasons. The results were published in JAMA Oncology.

Of the 9,639 patients with breast cancer, 41.1% were considered early-onset cases, with a diagnosis at age 45 or younger; 1.3% of breast cancer patients were male, and 13.7% had bilateral or multiple breast cancer. Of the 2,051 women with ovarian cancer, a smaller proportion had early-onset disease (21.7%).

The analysis found associations between breast cancer and four non-BRCA genes, with varying odds ratios (OR) for each. Mutations in the ATM gene had an OR for breast cancer of 2.97 (95% CI, 1.67–5.68; P = 4.02 × 10^-5). For the PALB2 gene, the OR was 5.53 (95% CI, 2.24–17.65; P = 6.50 × 10^-6). CHEK2 and MSH6 were also significantly associated with increased breast cancer risk.

For ovarian cancer, MSH6 was again associated with increased risk, with an OR of 4.16 (95% CI, 1.95–9.47). ATM was also associated with increased risk, with an OR of 2.85 (95% CI, 1.30–6.32), and the research confirmed previously reported associations between ovarian cancer risk and RAD51C and TP53. Several other genes that were previously reported to be associated with ovarian cancer risk showed no such association, including BRIP1, RAD51D, CDKN2A, and several others.

“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,” the authors concluded. “These results, therefore, have the potential to serve as the foundation for future epidemiologic, clinical, or functional studies… and to inform comprehensive genetic testing and clinical practice.”

In an accompanying editorial, authors led by Stephanie L. Greville-Heygate, MSc, of the University of Southampton in the United Kingdom, wrote that the study “demonstrates the powerful potential of genomic technology to expand our current understanding of cancer susceptibility genes and their phenotypes.” They cautioned, though, that diagnostic genetic testing should have demonstrable clinical utility, and some of the new susceptibility genes may not meet that criteria as of yet.

“Although there is accumulating evidence to support genomic testing for hereditary breast or ovarian cancer, it is important to recognize that cancer risks conferred by constitutional genotype are modifiable by polygenic factors and environmental exposures,” they wrote. “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 an individual may possess.”