The study also found that 14% of women in this large clinical sample had a least one significant genetic mutation, reported Allison Kurian, MD, of Stanford University Cancer Institute in Stanford, Calif., and colleagues.
“And nearly one-third of the mutations we found were not related to BRCA1/2 or Lynch syndrome, the things we typically think of in ovarian cancer, but were in fact were in other genes,” she told MedPage Today. The findings were presented at the American Society of Clinical Oncology annual meeting.
The results confirmed the effect of genes commonly understood to be associated with ovarian cancer such as STK11, BRCA1, TP53, and RAD51C/D.
“But the ones that are perhaps of more interest here are genes that we think of as being breast cancer genes, and aren’t really sure about the associated ovarian cancer risk,” Kurian said. “And of course that’s very relevant clinically because if a person is at high risk of ovarian cancer through these genes, she might consider risk-reducing interventions like preventive surgery.”
The participants, some with ovarian cancer, some with other cancers, and some at risk, were assessed with the Myriad myRiskR hereditary cancer test that screens for mutations associated with eight cancers: breast, ovarian, and endometrial, as well as colorectal, pancreatic, gastric prostate, and melanoma.
The study used multiple-gene germline sequencing to assess hereditary cancer risk in 95,561 women with a panel of 25 genes: APC, ATM, BARD1, BMPR1A, BRCA1/2, BRIP1, CDH1, CDK4, CHEK2, MLH2, MSH2, MSH6, MYH, NBN, P14ARF, P16, PALB2, PMS2, PTEN, RAD51C, RAD51D, SMAD4, STK11, and TP53.
Multivariable regression analysis examined the association between pathogenic/suspected pathogenic mutations and personal ovarian cancer history. Independent variables were age, personal or family cancer history, and ancestry.
The sequencing detected mutations in 6,775 (7%) patients. Of these, 3,007 (44%) were in BRCA1/2 and 3,768 (56%) in a mix of other genes. A significant association with personal ovarian cancer history was found for the following 11 genes: ATM, BRCA1, BRCA2, BRIP1, MLH1, MSH2, MSH6, NBN, STK11, RAD51C, and RAD51D.
“If confirmed in other studies, these newly identified genes will be important to consider in genetic counselling and in evaluating patients with ovarian cancer,” Kurian said.
Gene-specific estimates of elevated ovarian cancer risk ranged from about twofold or less for mutations in ATM, BRIP1, NBN, MSH2, and MSH6 to almost 12-fold for BRCA1 (95% CI9.99-14.0).
BRCA2 was associated with an odds ratio of 5.26 (95% CI 4.38-6.31). Surprisingly, STK11 came in at an OR of 41.9, albeit with very broad confidence intervals (5.55-315).
“STK11 has been known to carry some risk, but 40-fold feels like a bit of an outlier, so this will need confirmation going forward,” Kurian said. She added that STK11 gene has been primarily associated with the intestinal hamartomatous polyposis of Peutz-Jeghers syndrome.
The lowest ovarian cancer risk was associated with genes P16 (OR 0.56) and BARD (OR 0.59).
If the risks conferred by such new mutations are confirmed in other datasets, they could change management guidelines and improve outcomes for at-risk individuals.
Commenting on the study for MedPage Today, Linda R. Mileshkin, MD, of Peter MacCallum Cancer Centre in Melbourne, Australia, said, ” These findings are certainly interesting because they come from a very large dataset, but the trouble is, the dataset is unique and potentially biased in terms of risk compared with the general population. Moving forward, I’d like to see some proper case-control or kindred studies to better understand what the real impact of some of these lower-risk genes is.”
Mileshkin added that in clinical terms “we don’t know how to respond very well to this information in practice. Say you have a risk of 1.5 and testing finds a gene that raises your risk by 3%, what do you actually do with that information?”
Last year, Kurian’s group reported on multigene panel testing for hereditary breast and ovarian cancer risk in 1,046 participants, and concluded that this rapidly evolving tool will impact the care of substantially more women than BRCA1/2 testing alone.
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