In the Journals

Germline mutations found in sporadic pancreatic cancer

Researchers observed germline mutations in pancreatic cancer susceptibility genes among patients with pancreatic cancer who did not have significant family history of the disease, according to study results.

Inherited gene mutations in BRCA2, ATM, PALB2, CDKN2A, PRSS1, STK11, MLH1 and MSH2 are known to contribute to pancreatic cancer in patients with familial pancreatic cancer.

However, the extent to which these deleterious mutations contribute to risk in those without a family history had not been well known.

To define the prevalence of these germline mutations in patients without a family history, Michael Goggins, MD, professor of pathology, medicine and oncology at The Johns Hopkins University School of Medicine, director of the pancreatic cancer early detection laboratory and attending physician in medicine in the division of gastroenterology and hepatology at The Johns Hopkins Hospital, and colleagues sequenced 32 genes in DNA from normal tissue from 854 patients with pancreatic ductal adenocarcinoma. Researchers compared these findings with those from 288 patients with other pancreatic and periampullary neoplasms and 51 patients with non-neoplastic diseases who underwent pancreatic resection between 2000 and 2015.

“There is considerable potential clinical utility to identifying a germline susceptibility gene in a patient with pancreatic cancer,” Goggins and colleagues wrote. “Mutation carriers with pancreatic cancer may have more options for personalized medicine directed against the genetic drivers of their cancer, and their family members may benefit from cancer screening and cancer prevention strategies for pancreatic and extrapancreatic cancers. Relatives of patients with apparently sporadic pancreatic cancer are at increased risk for mortality from other cancers.”

Overall, 33 (3.9%; 95% CI, 3-5.8) of the patients with pancreatic cancer harbored deleterious germline mutations. These included 31 mutations implicated in familial pancreatic cancer risk: BRCA2 (n = 12), ATM (n = 10), BRCA1 (n = 3), PALB2 (n = 2), MLH1 (n = 2), CDKN2A (n = 1) and TP53 (n = 1).

Patients who harbored these genes had a significantly younger age at diagnosis than patients without an identifiable susceptibility gene mutation (60.8 years ± 10.6 vs. 65.1 years ± 10.1; P = .03).

Two patients harbored mutations in candidate pancreatic cancer susceptibility genes BUB1B and BUB3.

Three additional patients harbored deleterious mutations in another cancer susceptibility gene — CDH1, RAD51D or RAD51B — all of which have uncertain significance for pancreatic cancer.

Eighty-two percent of patients with deleterious germline mutations had a family history of other cancers, but only five patients (15%) had family history that suggested familial cancer syndrome. Eighteen of the 33 mutation carriers had a first- or second-degree relative with breast cancer, six had a family history of prostate cancer, three had a family history of ovarian cancer and only three had a family history of pancreatic cancer.

In comparison, 117 of the 818 patients (14.3%) without a germline mutation had a family history of pancreatic cancer.

Significantly fewer patients with diagnoses other than pancreatic ductal adenocarcinoma had an identifiable deleterious germline mutation (n = 5 of 339; 1.5%; P = .02). All five of these patients had another malignancy, including cholangiocarcinoma, renal cell carcinoma with pancreatic metastasis, duodenal gastrointestinal stromal tumor and lymphoma.

Researchers identified no deleterious mutations in any other of the other disease control cases.

The substantial finding of deleterious germline mutations in susceptibility genes in apparently sporadic pancreatic cancer could justify routine gene screening in all patients with the disease, according to the researchers.

“However, offering widespread genetic testing for patients with pancreatic cancer has significant challenges, not the least being that patients should undergo genetic counseling before and after such testing to provide understanding and reassurance and to avoid harm,” the researchers wrote. “Unfortunately, there are not enough genetic counselors to provide this service.

“Because cancer genetics risk assessment is not a routine component of pancreatic cancer care, it would be valuable to undertake studies to determine the benefits and challenges of incorporating risk assessment and gene testing into routine pancreatic cancer practice,” they added. – by Alexandra Todak

Disclosure s: Goggins reports he has patents with Myriad Genetics. Other researchers also report patents with Myriad Genetics, one researcher reports a leadership role with miDIAGNOSTICS, and one researcher owns stock in 22nd Century Group.

Researchers observed germline mutations in pancreatic cancer susceptibility genes among patients with pancreatic cancer who did not have significant family history of the disease, according to study results.

Inherited gene mutations in BRCA2, ATM, PALB2, CDKN2A, PRSS1, STK11, MLH1 and MSH2 are known to contribute to pancreatic cancer in patients with familial pancreatic cancer.

However, the extent to which these deleterious mutations contribute to risk in those without a family history had not been well known.

To define the prevalence of these germline mutations in patients without a family history, Michael Goggins, MD, professor of pathology, medicine and oncology at The Johns Hopkins University School of Medicine, director of the pancreatic cancer early detection laboratory and attending physician in medicine in the division of gastroenterology and hepatology at The Johns Hopkins Hospital, and colleagues sequenced 32 genes in DNA from normal tissue from 854 patients with pancreatic ductal adenocarcinoma. Researchers compared these findings with those from 288 patients with other pancreatic and periampullary neoplasms and 51 patients with non-neoplastic diseases who underwent pancreatic resection between 2000 and 2015.

“There is considerable potential clinical utility to identifying a germline susceptibility gene in a patient with pancreatic cancer,” Goggins and colleagues wrote. “Mutation carriers with pancreatic cancer may have more options for personalized medicine directed against the genetic drivers of their cancer, and their family members may benefit from cancer screening and cancer prevention strategies for pancreatic and extrapancreatic cancers. Relatives of patients with apparently sporadic pancreatic cancer are at increased risk for mortality from other cancers.”

Overall, 33 (3.9%; 95% CI, 3-5.8) of the patients with pancreatic cancer harbored deleterious germline mutations. These included 31 mutations implicated in familial pancreatic cancer risk: BRCA2 (n = 12), ATM (n = 10), BRCA1 (n = 3), PALB2 (n = 2), MLH1 (n = 2), CDKN2A (n = 1) and TP53 (n = 1).

Patients who harbored these genes had a significantly younger age at diagnosis than patients without an identifiable susceptibility gene mutation (60.8 years ± 10.6 vs. 65.1 years ± 10.1; P = .03).

Two patients harbored mutations in candidate pancreatic cancer susceptibility genes BUB1B and BUB3.

Three additional patients harbored deleterious mutations in another cancer susceptibility gene — CDH1, RAD51D or RAD51B — all of which have uncertain significance for pancreatic cancer.

Eighty-two percent of patients with deleterious germline mutations had a family history of other cancers, but only five patients (15%) had family history that suggested familial cancer syndrome. Eighteen of the 33 mutation carriers had a first- or second-degree relative with breast cancer, six had a family history of prostate cancer, three had a family history of ovarian cancer and only three had a family history of pancreatic cancer.

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In comparison, 117 of the 818 patients (14.3%) without a germline mutation had a family history of pancreatic cancer.

Significantly fewer patients with diagnoses other than pancreatic ductal adenocarcinoma had an identifiable deleterious germline mutation (n = 5 of 339; 1.5%; P = .02). All five of these patients had another malignancy, including cholangiocarcinoma, renal cell carcinoma with pancreatic metastasis, duodenal gastrointestinal stromal tumor and lymphoma.

Researchers identified no deleterious mutations in any other of the other disease control cases.

The substantial finding of deleterious germline mutations in susceptibility genes in apparently sporadic pancreatic cancer could justify routine gene screening in all patients with the disease, according to the researchers.

“However, offering widespread genetic testing for patients with pancreatic cancer has significant challenges, not the least being that patients should undergo genetic counseling before and after such testing to provide understanding and reassurance and to avoid harm,” the researchers wrote. “Unfortunately, there are not enough genetic counselors to provide this service.

“Because cancer genetics risk assessment is not a routine component of pancreatic cancer care, it would be valuable to undertake studies to determine the benefits and challenges of incorporating risk assessment and gene testing into routine pancreatic cancer practice,” they added. – by Alexandra Todak

Disclosure s: Goggins reports he has patents with Myriad Genetics. Other researchers also report patents with Myriad Genetics, one researcher reports a leadership role with miDIAGNOSTICS, and one researcher owns stock in 22nd Century Group.