Multigene Hereditary Cancer Panels Reveal High-Risk Pancreatic Cancer Susceptibility Genes.

PURPOSE

The relevance of inherited pathogenic mutations in cancer predisposition genes in pancreatic cancer is not well understood. We aimed to assess the characteristics of patients with pancreatic cancer referred for hereditary cancer genetic testing and to estimate the risk of pancreatic cancer associated with mutations in panel-based cancer predisposition genes in this high-risk population.

METHODS

Patients with pancreatic cancer (N = 1,652) were identified from a 140,000-patient cohort undergoing multigene panel testing of predisposition genes between March 2012 and June 2016. Gene-level mutation frequencies relative to Exome Aggregation Consortium and Genome Aggregation Database reference controls were assessed.

RESULTS

The frequency of germline cancer predisposition gene mutations among patients with pancreatic cancer was 20.73%. Mutations in and were associated with high pancreatic cancer risk (odds ratio, > 5), and mutations in were associated with moderate risk (odds ratio, > 2). In a logistic regression model adjusted for age at diagnosis and family history of cancer, and mutations were associated with personal history of breast or pancreatic cancer, whereas mutations were associated with family history of breast or pancreatic cancer.

CONCLUSION

These findings provide insight into the spectrum of mutations expected in patients with pancreatic cancer referred for cancer predisposition testing. Mutations in eight genes confer high or moderate risk of pancreatic cancer and may prove useful for risk assessment for pancreatic and other cancers. Family and personal histories of breast cancer are strong predictors of germline mutations.