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Inherited Mutations in DNA-Repair Genes Found in Advanced Prostate Cancers

, by NCI Staff

Like a watch wrapped around a wrist, a special enzyme encircles the double helix to repair a broken strand of DNA. Without molecules that can mend such breaks, cells can malfunction, die, or become cancerous.

Credit: NIGMS / Tom Ellenberger, Washington University School of Medicine

Nearly 12% of men with advanced prostate cancer have inherited mutations in genes that play a role in repairing damaged DNA, according to a new study. Inherited mutations in DNA-repair genes—including BRCA2, ATM, and CHEK2—are associated with an increased risk of several other cancers, including breast, ovarian, and pancreatic cancer. 

“This finding offers a new window into understanding how metastatic prostate cancers develop,” said Peter Nelson, M.D., of the Fred Hutchinson Cancer Research Center, who co-led the study.

Reporting their results in the New England Journal of Medicine on July 6, the researchers noted that, in the future, men who have prostate cancer with these inherited mutations may be candidates for particular treatments, such as drugs that target molecular changes associated with defects in DNA repair.

Confirming an Unexpected Result

The study was sparked by an unexpected result of an earlier study. As the researchers were profiling genomic changes in metastatic prostate cancers, they sequenced DNA from normal tissues in the same patients for comparison purposes. They found that 8% of men with metastatic prostate cancer in that study had inherited a mutation in a DNA-repair gene.

The proportion of inherited, or germline, mutations was so unexpectedly high that the researchers conducted the current study in part to see whether the high frequency of mutations was “reproducible when we were looking at a large population of men,” explained coauthor Colin C. Pritchard, M.D., Ph.D., of the University of Washington.

The answer, he added, “was a resounding yes.”

In fact, the frequency of germline mutations in 16 DNA-repair genes among 692 men with metastatic prostate cancer turned out to be even higher—11.8%. The researchers detected harmful germline mutations in a DNA repair gene among 82 of the 692 participants.

The frequency of inherited DNA-repair gene mutations in men in the study was higher than the prevalence of 4.6% among 499 men with localized prostate cancer who participated in The Cancer Genome Atlas project, the researchers noted.

“These findings raise the possibility that a high proportion of men with metastatic prostate cancer—1 in 8—may have germline mutations in DNA-repair genes,” said James Gulley, M.D., Ph.D., chief of the Genitourinary Malignancy Branch in NCI’s Center for Cancer Research, who was not involved in the research.

“DNA-repair genes may play a role in the progression to metastatic prostate cancer, and more research should be done to look at mutations in these genes in men with prostate cancer,” Dr. Gulley added.

Potential Treatment Options

Given the high frequency of DNA-repair gene mutations in prostate cancer and the potential for information about these mutations to inform treatment decisions, Dr. Nelson recommends that all patients with metastatic prostate cancer discuss the possibility of germline testing for inherited mutations in DNA-repair genes with their physicians.

“The potential for new treatments for these patients is really exciting,” said Dr. Pritchard. 

For example, drugs known as PARP inhibitors, which block an enzyme that helps repair damaged DNA, have been approved for some patients with ovarian cancer and are being evaluated in men with prostate cancer. One of these agents, olaparib (Lynparza™) (Lynparza, is approved for certain patients with ovarian cancer whose tumors have mutations in the BRCA1 or BRCA2 genes.

Although PARP inhibitors have not yet been approved for prostate cancer, the Food and Drug Administration in January granted Breakthrough Therapy designation for olaparib for treating certain patients with prostate cancer. The decision was based on results from an early-stage clinical trial that showed a high response rate to olaparib among men with metastatic prostate cancer whose tumors did not respond to standard treatments and had defects in DNA-repair genes.

Another potential treatment is platinum-based chemotherapy, which has been tested in women with breast and ovarian cancers that have mutations in DNA-repair genes. A recent case report describes three patients with metastatic prostate cancer and BRCA2 mutations who had exceptional responses to platinum-based chemotherapy, the study authors noted.

More research is needed to prospectively evaluate platinum-based chemotherapy in patients with metastatic prostate cancer, noted Dr. Nelson, who presented the study results in June at the annual meeting of the American Society of Clinical Oncology (ASCO). Nonetheless, he added, the findings have pointed “to potential treatments that we would not have thought of otherwise.”

Additional Types of Cancer 

Among all patients in the study (with and without germline DNA-repair gene mutations), 22% had a first-degree relative with prostate cancer. Some relatives had other types of cancer, including breast cancer, ovarian cancer, leukemia, lymphoma, pancreatic cancer, and other gastrointestinal cancers.

For instance, 51 of the 72 patients with an inherited DNA-repair gene mutation (71%) had a first-degree relative with a cancer other than prostate cancer, whereas 270 of the 537 patients without such a mutation (50%) did.

“The types of cancer in some of the family members of men with DNA-repair gene mutations were striking,” said coauthor Michael Walsh, M.D., of Memorial Sloan Kettering Cancer Center. “We don’t typically think of leukemia and lymphoma, for example, as being associated with mutations in DNA-repair genes.”

The researchers have begun to investigate these cases to better understand the association between inherited DNA-repair gene mutations and various types of cancer.

“Based on our results,” said Dr. Pritchard, “it looks as though asking men with metastatic prostate cancer about a family history of other cancers might be just as important as asking about their family history of prostate cancer.”

“Sentinels” for Family Members

The findings may also have implications for family members who may have unknowingly inherited cancer-predisposing genetic mutations. Men with inherited DNA-repair gene mutations could serve as “sentinels” for family members who may carry the same genetic alterations, said Dr. Nelson.

For example, close female relatives of a patient with metastatic prostate cancer who carries an inherited harmful BRCA1 mutation might want to be tested for the presence of the same mutation. If the relatives are found to have the mutation, they could consider taking steps to reduce their risk of developing breast or ovarian cancer.

Dr. Nelson noted that the investigators were conservative in their assessments of potential cancer-related mutations in DNA-repair genes, so the frequency of these mutations could be even higher. The patients in the study were nearly all white, however, and future studies need to include men of different racial and ethnic backgrounds, he added.

Guidelines on Genetic Screening?

Tests for inherited mutations in DNA-repair genes are commercially available. But Dr. Walsh cautioned that, as with any type of genetic testing, “it is important for patients to go to centers that are familiar with the tests and how to interpret the results.”

At the ASCO meeting, Judy Garber, M.D., M.P.H., of the Dana-Farber Cancer Institute discussed Dr. Nelson’s presentation. She supported his recommendation to test all patients with metastatic prostate cancer for inherited mutations in DNA-repair genes.

A frequency of 11.8% is above the criteria for recommending genetic testing in nearly all European countries and “certainly for insurance coverage [of testing] in the United States,” Dr. Garber said. There has been more interest in testing women for mutations in genes such as BRCA2 than men, she continued, adding: “It’s time we brought in the men.”

By her calculation, only 4 of the 190 clinical trials involving PARP inhibitors include men with metastatic prostate cancer. Addressing the audience, she said, “You have a lot of opportunity, and now you have a real clue that you need to move forward.” 

In the meantime, some of the study authors have already begun to screen patients with metastatic prostate cancer for the mutations. “We are optimistic that this study and others will lead experts who create guidelines to takes a closer look at DNA-repair genes and metastatic prostate cancer,” said Dr. Pritchard.