In a recent study, researchers established that heritable germline mutations in six genes associated with pancreatic cancer were present in 5.5% of patients with the disease, findings that support broader genetic testing of patients with pancreatic cancer and their family members.

Pancreatic cancer may have a stronger hereditary component than was previously thought: In the largest study to date, researchers established that germline mutations in six genes associated with pancreatic cancer occurred in 5.5% of patients with the disease, including 5.2% of patients without a family history, findings that support broader genetic testing (JAMA 2018;319:2401–9).

In recent years, smaller studies have shown that patients with pancreatic cancer are more likely to have certain germline mutations, says Fergus Couch, PhD, of the Mayo Clinic in Rochester, MN, a senior author on the new study. However, the size and design of these studies have prevented them from definitively establishing the prevalence of these mutations, which is what Couch and his team set out to do.

The researchers retrospectively analyzed DNA from 3,030 patients with pancreatic cancer and compared alterations in 21 cancer-predisposition genes with genetic data from 123,136 healthy controls. Germline mutations in six genes were significantly associated with pancreatic cancer, occurring in 5.5% of patients. Overall, CDKN2A mutations were 12.3 times more common among patients with the disease, whereas TP53, MLH1, BRCA2, and ATM mutations were 5.7 to 6.7 times more common, and BRCA1 mutations were 2.6 times more common.

Additionally, only 17% of patients in the study who had these heritable germline mutations would have been flagged for genetic testing based on current criteria, which require a family history of the disease.

Clearly, Couch says, clinicians should not rely on family history alone to determine whether patients should undergo genetic testing after being diagnosed with pancreatic cancer. “We should be considering other methods for selecting people for testing,” he says. In addition, because more than 5% of patients with pancreatic cancer have germline mutations, he wonders if steps can be taken to identify those at risk ahead of time in order to diagnose them at an earlier stage, or prevent them from developing the disease altogether.

Sapna Syngal, MD, MPH, of Dana-Farber/Harvard Cancer Center in Boston, MA, who wasn't involved in the study, praises it for “emphasizing that there is a significant number of pancreatic cancer patients who have an inherited cause for their cancer development.” Syngal, who co-authored an editorial on the study, thinks all patients with pancreatic cancer should undergo genetic testing at diagnosis (JAMA 2018;319:2383–5).

“If you have a mutation, then you or your family members who carry that mutation could be at risk for hereditary pancreas cancer, but also other cancers, such as breast or ovarian or colon, depending on what the gene is,” she explains. Findings could prompt relatives to focus on cancer surveillance and prevention.

Syngal is a member of a Stand Up To Cancer-Lustgarten Foundation Pancreatic Cancer Interception Dream Team that focuses on early detection of pancreatic cancer in high-risk individuals. In an upcoming study, the team will conduct genetic testing on family members of patients with germline mutations and then enroll those who carry the genetic aberrations in screening studies.

For Matthew Yurgelun, MD, of Dana-Farber/Harvard Cancer Center, who also wasn't involved in the study, “showing that these mutations are substantially overrepresented in the pancreatic cancer cases versus random controls proves some degree of causation—and gives you a sense as to what the magnitude of that link is.”

There are also emerging therapeutic implications for patients, says Yurgelun. For example, preliminary evidence suggests that PARP inhibitors may be an effective option for patients with pancreatic cancer who have BRCA1 and BRCA2 mutations.

“As time goes by, [these germline mutations] will point to more ways we can deliver personalized therapies to these pancreatic cancer patients,” he says. –Catherine Caruso

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