Beyond BRCA: New Predisposition Genes Linked to Breast, Ovarian Cancers

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Researchers identified MSH6 and ATM as possible new predisposition genes that confer a moderate risk for breast and ovarian cancers, respectively.
Researchers identified MSH6 and ATM as possible new predisposition genes that confer a moderate risk for breast and ovarian cancers, respectively.

In addition to confirming several well-known cancer predisposition genes, investigators found that novel genes MSH6 and ATM were significantly linked to moderate risk in breast cancer and ovarian cancer, respectively, according to a study published in JAMA Oncology.

A team of researchers from Ambry Genetics Inc. performed whole-exome sequencing to investigate if non-BRCA cancer genes that are not commonly included in multigene panel tests are associated with breast and ovarian cancer risk — and they attempted to ascertain the degree of this risk.

Patients across 1200 hospitals who had clinical features of breast cancer, ovarian cancer, or both were asked to participate in genetic testing (11,416 individuals). An additional 3988 individuals (serving as controls) were asked to participate in genetic testing for noncancer conditions.

Approximately 41% (3960 individuals) of the 9639 patients with breast cancer had early-onset cases (aged ≤ 45 years at diagnosis). The age at early-onset diagnosis was higher in men than in women (average age of diagnosis: 61.8 years vs 48.6 years, respectively). Nearly 22% (445 of 2015) of the ovarian cancer patients were diagnosed at age 45 or younger.

The investigators reported 4 non-BRCA genes significantly associated with an increased risk of breast cancer: ATM (odds ratio [OR], 2.97), CHEK2 (OR, 2.19), PALB2, (OR, 5.53), and MSH6 (OR, 2.59). In addition, 4 non-BRCA genes thought to be associated with increased ovarian cancer risk were identified: MSH6 (OR, 4.16), RAD51C (OR, not estimable; false-discovery rate–corrected P = .004), TP53 (OR, 18.50), and ATM (OR, 2.85).

Neither MRN complex genes nor CDKN2A was associated with increased breast or ovarian cancer risk. Previously reported associations between ovarian cancer susceptibility genes BRIP1, RAD51C, and RAD51D and breast cancer were not supported in this analysis; mismatch repair genes MSH2 and PMS2 were also found not to be associated with breast cancer risk.

“In addition to confirming several well-known breast or ovarian cancer gene associations, this study identified MSH6 and ATM as possible moderate-risk breast and ovarian cancer predisposition genes, respectively,” the authors wrote.

“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 investigators concluded. “These results, therefore, 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.”

Disclosure: This study was funded by Ambry Genetics Inc.  

Reference

  1. Lu H-M, Li S, Black MH, et al. Association of breast and ovarian cancers with predisposition genes identified by large-scale sequencing. [published online August 16, 2018]. JAMA Oncol. doi: 10.1001/jamaoncol.2018.2956

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