Fergus J. Couch
Researchers identified mutations in six genes associated with pancreatic cancer, according to study results published in JAMA.
“Cancer predisposition gene testing is useful for identifying individuals who may benefit from screening, prevention and early detection of breast, ovarian and colorectal cancer and may be beneficial for individuals at risk [for] pancreatic cancer,” Fergus J. Couch, PhD, consultant in the division of experimental pathology and laboratory medicine at Mayo Clinic in Rochester, Minnesota, and colleagues wrote. “Family members of those with germline predisposition gene mutations may also benefit from enhanced cancer screening and prevention strategies.”
The researchers performed a case-control analysis to identify genes associated with pancreatic cancer, and they conducted a longitudinal analysis of patients who had pancreatic cancer to determine prognosis.
A total of 3,030 adults with pancreatic cancer enrolled in the study at Mayo Clinic from Oct. 12, 2000, and March 31, 2016. Follow-up continued through June 22, 2017. The control cohort included 123,136 individuals who had exome sequence data from the Genome Aggregation Database, and 53,105 individuals from the Exome Aggregation Consortium Database.
When Couch and colleagues compared 3,030 patients with pancreatic cancer to controls, mutations in six genes appeared significantly associated with pancreatic cancer: CDKN2A (0.3% of cases vs. 0.2% of controls; OR = 12.33; 95% CI, 5.43-25.61), TP53 (0.2% vs. 0.02%; OR = 6.7, 95% CI, 2.52-14.95), MLH1 (0.13% vs. 0.02%; OR = 6.66; 95% CI, 1.94-17.53), BRCA2 (1.9% vs. 0.3%; OR = 6.2; 95% CI, 4.62-8.17); ATM (2.3% vs. 0.37%; OR = 5.71; 95% CI, 4.38-7.33) and BRCA1 (0.6% vs. 0.2%; OR = 2.58; 95% CI, 1.54-4.05).
Researchers observed a mutation in one of the six predisposition genes among 27 of 343 patients (7.9%; 95% CI, 5.3%-11.2%) with a family history of pancreatic cancer and 140 of 2,687 patients (5.2%; 95% CI, 4.4%-6.1%) with no family history, indicating family history of pancreatic cancer did not indicate the presence of 83.8% of mutations.
Also, 40 of 495 patients (8.1%; 95% CI, 5.8%-10.8%) with another prior primary cancer diagnosis harbored a mutation.
Researchers observed significant associations between mutations in the six predisposition genes and advanced stage of disease (P = .04), personal history of other cancers (OR = 1.67; 95% CI, 1.17-2.48), family history of breast cancer (OR = 1.58; 95% CI, 1.11-2.23) and family history of common epithelial cancers (OR = 1.4; 95% CI, 1.01-1.92).
Also, patients with a mutation in these one of these genes were diagnosed at a younger age (62.5 years vs. 65.5 years, P < .001), especially with a BRCA2 mutation alone (mean age, 60.5 years vs. 63.3 years; P = .01).
Median OS for patients with mutation in the six genes was 13.6 months, compared with 11.4 months among those without mutations, which did not represent a significant difference (HR = 0.86; 95% CI, 0.72-1.02).
These findings suggest it is appropriate to consider screening for inherited susceptibility for cases of pancreatic cancer, Sapna Syngal, MD, MPH, professor of medicine at Harvard Medical School, and C. Sloane Furniss, PhD, research scientist at Dana-Farber Cancer Institute, wrote in an accompanying editorial.
“Given the devastating outcomes of pancreatic cancer, the real potential benefit for targeted therapies and, even more importantly, the potential for cancer prevention in at-risk relatives, it is time to consider implementation of germline genetic testing for all patients with pancreatic cancer,” they wrote. “Because the window of opportunity is limited, discussion about genetic testing needs to happen at or shortly after diagnosis as part of the standard management of newly diagnosed pancreatic ductal adenocarcinoma.” – by Andy Polhamus
Disclosures: Couch reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures. Syngal reports personal fees from Myriad Genetics Inc. Furniss reports no relevant financial disclosures.