Abstract
A new study finds that 11.8% of men with metastatic prostate cancer carry mutations in DNA repair genes. The mutations were more than five times as prevalent in men with metastatic disease as in men with localized prostate cancer. Although relatives of the men weren't more likely to have prostate cancer, they were more likely to have breast, ovarian, and other cancers.
Nearly 12% of men with metastatic prostate cancer carry germline mutations in DNA repair genes, a new study finds. Testing these men for the alterations might suggest effective treatments—and identify family members who are vulnerable to other cancers.
The overall incidence of mutated DNA repair genes in prostate cancer is low. Only 1.2% to 1.8% of men with the disease show BRCA2 mutations, for instance. However, a study published last year by Peter Nelson, MD, PhD, of the Fred Hutchinson Cancer Research Center in Seattle, WA, and colleagues suggested that these mutations are more abundant in metastatic disease. The researchers catalogued mutations in tumor DNA from 150 men with metastatic prostate cancer, using the patients' germline DNA as controls. They noticed that 8% of the men harbored germline mutations in DNA repair genes. “That 8% number was very surprising,” says Nelson.
Looking to confirm their results, Nelson and colleagues performed a new analysis involving 692 men with metastatic prostate cancer. After sequencing patients' germline DNA, the researchers searched for variants in a panel of 20 repair genes and found that 11.8% of the men had mutations in 16 of them. BRCA2 mutations were the most common, occurring in 5.3% of the patients. Other mutated repair genes included ATM, BRCA1, RAD51D, and CHEK2.
Because these germline mutations are likely to occur in the patients' relatives, increasing their risk of cancer, the researchers analyzed the medical history of the men's family members. The prevalence of prostate cancer was the same in the relatives of the men who carried DNA repair mutations as in the relatives of men who didn't. However, family members of the men with DNA repair mutations did have a higher incidence of other cancers, including breast, ovarian, and gastrointestinal cancers, suggesting that the mutations promote these malignancies.
To determine whether the frequency of DNA repair gene mutations differed between men with localized and metastatic cancer, the researchers used sequencing data from The Cancer Genome Atlas on 499 men with prostate cancer. Men with metastatic disease were more than five times as likely to harbor germline mutations in DNA repair genes as patients with localized low-risk or intermediate-risk tumors, and more than twice as likely as men with localized high-risk tumors, the scientists found.
“It's an important result for prostate cancer,” says David Olmos, MD, PhD, of the Spanish National Cancer Research Centre in Madrid, who wasn't connected to the study. One reason the findings are notable: Testing men with metastatic disease could pinpoint families with inherited mutations that confer susceptibility to other cancers, allowing them to receive frequent screening or take steps to reduce their risk, he says.
The findings also point to treatments for men with the mutations. They may respond to platinum-based drugs such as carboplatin, which is effective against ovarian and breast cancers with BRCA1 or BRCA2 mutations, and PARP1 inhibitors such as olaparib (Lynparza; AstraZeneca), which is approved to treat ovarian cancer with those gene mutations. Although olaparib hasn't been approved for prostate cancer, researchers are planning phase III trials for patients with advanced disease, Nelson notes. –Mitch Leslie
