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Mayo, Ambry Genetics Analyze Large Cohort to Refine Breast Cancer Risk Genes on NGS Panels


SAN ANTONIO (GenomeWeb) – The Mayo Clinic and Ambry Genetics have collaborated to analyze the association of 21 known and candidate breast cancer predisposition genes in 65,000 patients and identified new genes that increase a woman's risk of developing breast cancer when mutated, concluding that other genes with unclear associations weren't associated with greater risk after all.

The aim of the collaboration was to better define the cancer risk associated with mutations in genes included in next-generation sequencing panels. "The field of hereditary cancer genetics has changed dramatically in the last four years," Fergus Couch, a geneticist at the Mayo Clinic and lead author of the study, said at the San Antonio Breast Cancer Symposium yesterday.

The availability of NGS panels enable screening for alterations in genes beyond BRCA1 and BRCA2 and can include up to 50 genes, but these tests often reveal variants of unknown significance and the role of some of these genes in breast cancer is unclear.

"The question is whether the genes on these panels are really driving breast cancer risk," Couch said. "Or whether they were put on the panel because there was really minimal evidence available in the literature but there was a possibility of them being involved in breast cancer."

He highlighted for example, that for BARD1, MRE11A, RAD50, and XRCC2 there is insufficient data on whether mutations confer disease risk, but studies have shown that mutations in PALB2, ATM, and CHEK2 do confer some risk but have wide confidence intervals. Therefore, when tests detect mutations in these genes, "we can't really give patients very specific risks for their cancers," Couch said. "All of this causes immense problems in the clinic, patients come in, mutations are found and it's really difficult to know hot to counsel the patients in terms of their risk."

Large studies like this are being performed more frequently with increasing adoption of NGS testing, shedding light on the clinical relevance of gene mutations rarely seen in patients before. A few months ago, at another oncology conference, researchers evaluated data from 100,000 women assessed on Myriad Genetics' myRisk Hereditary Cancer test to explore the magnitude of breast and ovarian cancer risk associated with mutations in 25 genes on the panel at the time of the study.

In that evaluation, researchers were able to report some novel findings, for example that mutations in ATM, which occur in 0.5 percent and 1 percent of breast cancer patients, also confer risk for ovarian cancer. Still, despite the size of the cohort, researchers said that the clinical significance of some genes remained uncertain.

For the present study, Couch and colleagues analyzed data from 65,000 patients who were diagnosed with breast cancer at the time Ambry tested them, out of 121,000 patients that the company assessed for their risk of hereditary cancer between March 2012 and June 2016. The genetic information came from any hereditary cancer multi-gene panel Ambry offered to a breast cancer patient, including BRCAplus, BreastNext, OvaNext, CancerNext, and CancerNext-Expanded, which include between five and 49 genes.  

Then, using various filtering steps, Couch's group analyzed the data of around 38,300 Caucasian breast cancer patients to obtain accurate cancer risk estimates for 21 genes, excluding BRCA1 and BRCA2, and compared it to control data from the Exome Aggregation Consortium (ExAC). There are differences between these two populations, Couch acknowledged, and further noted that because of insurance coverage criteria, patients tested by Ambry tend to be at high risk of cancer by personal or family history.

Approximately 6 percent of tested patients had mutations in 16 genes, with the majority of mutations showing up in ATM, CHEK2, and PALB2. Based on a comparison with ExAC, ATM and CHEK2 were found to be moderate-risk genes as determined by prior studies, while PALB2 was found to be a high-risk gene in the enriched population. BRIP1, Couch said, can be excluded as a high-risk marker, and should be considered "a low-risk, or maybe even a no-risk breast cancer gene."

The analysis revealed two genes — BARD1 and RAD51D — as new moderate-risk factors in breast cancer. MSH6 and CDKN2A were found to be potentially moderate risk genes, but even bigger cohorts are necessary to establish their association more definitively.

"Some these [genes] have been around a very long time," Couch said. "We've been aware of them, but we just never had the data or the numbers or the statistical power in our studies to establish some of these genes as breast cancer risk factors."

Additionally, the study revealed that MRE11A, NBN, RAD50, and RAD51C weren't really breast cancer risk genes, though they are readily included in most NGS panels. MRE11A, NBN, and RAD50 are involved in DNA repair and seen in a small number of families around the world, and so were thought to confer breast cancer risk. "When you have a study of the magnitude we have here, you clearly see there is no increased risk for breast cancer," Couch said. Meanwhile, RAD51C is an ovarian cancer risk gene, he added, but the data show really no risk associated with breast cancer.

The latest National Comprehensive Cancer Network guidelines already recommend consideration of MRI screening for women who have mutations in ATM, CHEK2, PALB2, and a number of other genes. The data from Couch's group and larger studies could spur the addition of BARD1, MSH6, and RAD51D to that list of genes. Risk-reducing mastectomy is also an option discussed in the guidelines for patients with mutations in various genes, including ATM and PALB2, and Couch felt that CHEK2 could possibly be added. Finally, the guidelines could also be updated, he said, to note the genes conferring no breast cancer risk that his team found.

"There will need to be additional studies done," Couch cautioned, before these findings can be applied to clinical decisions like mastectomy. He noted that there are ongoing investigations with matched controls that might further refine breast cancer risk associations of many of these genes.

Ambry said it would use data from this and other studies to improve its test panels. "We continuously evaluate the genes included on our panels to ensure their clinical validity and this data will be one of the pieces of data we use to perform this evaluation," Jill Dolinsky, Ambry’s senior manager of clinical research, told GenomeWeb.