A new case–control study published in JAMA finds that germline mutations in six cancer predisposition genes are significantly associated with pancreatic cancer. Of 3,030 patients with pancreatic ductal adenocarcinoma (PDAC), 5.5% had germline mutations in one of the six genes. Among the 3,030 patients, 7.9% of those with and 5.2% of those without a family history of PDAC had a mutation in one of the six genes.

Testing for cancer predisposition gene mutations can be valuable in optimizing cancer care, for example for prevention and screening. However, the utility of this approach in PDAC is still unclear. Chunling Hu and colleagues have now evaluated the association between inherited germline mutations in known cancer predisposition genes and the risk of PDAC. In their case–control study including 3,030 patients with PDAC at different disease stages, the researchers analysed patient sequencing data of 21 genes that are implicated in susceptibility to solid tumours in comparison with publicly available reference data from a total of 176,241 controls. Six genes were significantly associated with PDAC compared with controls: CDKN2A, TP53, MLH1, BRCA2, ATM and BRCA1. Overall, 5.5% of the tested patients had deleterious mutations in one of the six predisposition genes, and 7.9% of 343 patients with and 5.2% of 2,687 patients without family history of pancreatic cancer had a mutation in one of these six genes. Furthermore, among 495 patients who had previously been diagnosed with a different cancer, 8.1% had alterations in these genes.

5.5% of the tested patients had deleterious mutations in one of the six predisposition genes

Evaluation of patient characteristics showed that advanced disease stage, history of other cancers, family history of breast cancer or common epithelial cancers and younger age at diagnosis were significantly associated with mutations in the six predisposition genes. Specifically, BRCA2 alterations were significantly associated with an earlier age at PDAC diagnosis (mean age 60.5 years versus 63.3 years; P = 0.01). In addition, only patients with CDKN2A alterations were more likely to have a family history of pancreatic cancer (OR 7.91, 95% CI 2.19–28.57; P = 0.005). Analysis of mutation status and overall survival showed no statistical significance: median overall survival of patients with and without mutations was 13.6 months versus 11.4 months, respectively.

These findings provide new insights into the effect of germline mutations on the risk of developing PDAC and, pending further research, might inform future genetic testing guidelines for this disease.