Further support for germline genetic testing of pancreatic cancer patients
medwireNews: Germline mutations in six cancer predisposition genes are associated with pancreatic cancer, with approximately one in 20 patients harboring a mutation in at least one of these genes, shows a case–control study.
“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,” say the authors of an editorial accompanying the research in JAMA.
“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],” write Sapna Syngal and C Sloane Furniss (both from Dana-Farber Cancer Institute, Boston, Massachusetts, USA).
A total of 253 deleterious germline mutations in 19 cancer predisposition genes were detected among 8.2% of 3030 pancreatic cancer patients, drawn from the Mayo Clinic Biospecimen Resource for Pancreas Research.
Mutations in six genes – specifically, CDKN2A, TP53, MLH1, BRCA2, ATM, and BRCA1 – occurred significantly more frequently in patients with pancreatic cancer than in 123,136 controls with publicly available exome sequence data in the Genome Aggregation Database.
Of these, ATM germline mutations were most common, occurring in 2.30% of cases versus 0.37% of controls, equating to a significant 5.71-fold increased risk for pancreatic cancer, while mutations in MLH1 were least common, at 0.13% versus 0.02%, giving an odds ratio (OR) of 6.66.
The presence of CDKN2A mutations appeared to confer the highest risk for pancreatic cancer, with an OR relative to controls of 12.33, but these mutations did not occur frequently (0.30 vs 0.02%).
Altogether, 5.5% of the 3030 pancreatic cancer patients included in this study had deleterious mutations in at least one of these six predisposition genes, with rates of 7.9% and 5.2% among those with and without a family history of pancreatic cancer, respectively.
Study author Fergus Couch (Mayo Clinic, Rochester, Minnesota, USA) and co-workers also investigated factors that could predict the presence of mutations, and found significant associations with a personal history of other cancers (OR=1.67), a family history of breast cancer (OR=1.58), and a family history of epithelial cancers (OR=1.40).
“However, the specificity for mutations was too low for effective selection of patients for clinical genetic testing,” they comment.
The editorialists agree, writing that “[o]verall, the aggregate published data thus far suggest that although certain personal and family history characteristics are associated with increased likelihood of carrying a pancreatic susceptibility gene, the reliability of these variables is modest at best; thus, relying on such features is likely to miss a substantial proportion of patients who carry pancreatic cancer susceptibility genes.”
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