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Multiple pathogenic variants other than BRCA1/2 linked to increased risk for breast cancer
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Various inherited pathogenic variants other than BRCA1/2 appear linked to increased risk for breast cancer, according to results of a case–control study.
“We now have extra genes that predispose [women] to breast cancer in the population,” Fergus J. Couch, PhD, Zbigniew and Anna M. Scheller professor of medical research, and chair of the division of experimental pathology at Mayo Clinic in Rochester, Minnesota, told HemOnc Today. “These should be useful for testing of families and may prove useful for selecting women who can benefit from better screening for cancer using MRI.”
Improvements in DNA sequencing technology led to the development of multigene panels that target genes implicated in cancer susceptibility. These increase the likelihood of identifying cancer-predisposing variants and offer more advantages than single-gene testing. However, the risks for breast and other cancers associated with variants in many gene panels have not been established.
“Many of the genes on commercial hereditary cancer clinical genetic testing panels do not have defined roles in breast cancer,” Couch said. “In short, the involvement of several of the genes in breast cancer susceptibility has not been determined and, for other genes, we do not have accurate estimates of the level of risk associated with pathogenic mutations.”
Couch and colleagues used a nationwide dataset of 65,057 patients with breast cancer referred for hereditary genetic testing by Ambry Genetics Inc. between March 2012 and June 2016. Among these, 64,405 patients were women (mean age at diagnosis, 48.5 years). A total of 59.7% of patients developed breast cancer at age 50 years or younger. A majority of patients reported a family history of breast cancer (61.3%), colorectal cancer (23%) or ovarian cancer (13.2%).
“We sought to define the genes involved in breast cancer and to provide estimates of cancer risk for each of the genes that do predispose to breast cancer,” Couch said.
Researchers estimated the frequency of 21 inherited pathogenic variants from 21 genes in 58,798 eligible women with breast cancer. Researchers noted a subset of patients was not tested for all genes, so the frequencies of the variants from each of the 21 genes were combined to measure the overall frequency of pathogenic variation.
The combined frequency of pathogenic variants was 10.2% among 41,611 white women with breast cancer and 6.18% after the exclusion of BRCA1 and BRCA2. The most commonly mutated genes other than BRCA1/2 were CHEK2 (1.73%), ATM (1.06%) and PALB2 (0.87%).
After exclusion of BRCA1, BRCA2 and nonsyndromic genes CDH1, PTEN and TP53, five of 16 variants were associated with high or moderately increased risk for breast cancer. These included a high risk associated with the PALB2 gene (OR = 7.46; 95% CI, 5.12-11.19), and moderate risks associated with CHEK2 (OR = 1.48; 95% CI, 1.31-1.67) and ATM (OR = 2.78; 95% CI, 2.22-3.62) variants.
Although the link to cancer with those genes was “not surprising”, Couch said the addition of BARD1 (OR = 2.16; 95% CI, 1.31-3.63), RAD51D (OR = 3.07; 95% CI, 1.21-7.88) and MSH6 (OR = 1.93; 95% CI, 1.16-3.27) as moderate-risk breast cancer genes were an unexpected finding.
In addition, the researchers found that variants in MRE11A, NBN, RAD50, NF1, BRIP1, RAD51C and MLH1 genes were not linked to breast cancer.
“These have been thought to have a role in breast cancer for some time, so it is a surprise to find that they are not involved. ...[This] is also important because women found to carry mutations in these genes should not be using the mutations to drive their clinical management,” Couch said.
Although the risks may not be generalized to all mutation carriers, the researchers wrote this is “highly relevant” to patients with clinical histories suggestive of hereditary breast cancer predisposition.
“The ‘new’ breast cancer genes may now be useful for identifying women who can benefit from enhanced screening. ... These results will also be useful for identifying members of families who are at increased risk for breast cancer,” Couch said, adding that the data remain to be considered by the National Comprehensive Cancer Network.
The selection of women in the study may present a bias toward inclusion of high-risk individuals, Elias I. Obeid, MD, MPH, assistant professor of clinical genetics and medical oncology at Fox Chase Cancer Center, and colleagues wrote in a related editorial.
“Case selection in the study has a common bias: ascertainment bias,” Obeid and colleagues wrote. “Cases were women with a confirmed diagnosis of breast cancer and who, for the most part, met criteria current at the time for genetic testing based on their early age at diagnosis of breast cancer, type of breast cancer and/or family history. Therefore, in such a highly select sample of women with breast cancer diagnosis, these factors may lead to biased risk estimates that may not necessarily reflect actual or average risks associated with the genes tested.”
The authors noted that the most important finding by Couch and colleagues is the lack of association between various moderate-risk genes that appear on the breast cancer multigene tests and breast cancer risk.
“We are in immediate need of well-designed studies to provide further clarification of risk estimates for low-penetrance and modest-risk genes, as well as expanded guidelines on how to best manage these risks over the lifetime of the patient,” Obeid and colleagues wrote. – by Melinda Stevens
For more information:
Fergus J. Couch, PhD, can be reached at couch.fergus@mayo.edu.
Disclosures: Couch reports no relevant financial disclosures. Please see the full study for a complete list of all other authors’ relevant financial disclosures. Obeid and colleagues report no relevant financial disclosures.
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