It has been suggested that ~10% of pancreatic cancer has a familial basis 1, 2. Individuals with a family history of pancreatic cancer have an increased risk of developing both pancreatic and extrapancreatic malignancies, and an individual’s risk of developing pancreatic cancer can now be quantified based on their family cancer history 1, 3, 4.
While some of the aggregation of pancreatic cancer in families is due to chance, and some to shared environmental exposures such as cigarette smoking, it is now clear that much of this aggregation has a genetic basis 5. Several of the genes responsible for the familial clustering of pancreatic cancer have been discovered. For example, germline mutations in the BRCA2 gene cause familial breast cancer, and individuals with germline BRCA2 gene mutations have an approximately 3.5-fold increased risk of pancreatic cancer 6–12. Germline mutations in the p16/CDKN2A gene cause the Familial Atypical Multiple Mole Melanoma (FAMMM) syndrome, and these individuals have a 13 to 37-fold increased risk of pancreatic cancer 10, 13–23. Inherited mutations in the STK11 gene cause the Peutz-Jeghers syndrome, and individuals with Peutz-Jeghers have a 130-fold increased risk of pancreatic cancer 24–30. The discovery of these familial pancreatic cancer genes has helped identify cellular pathways important for the development of pancreatic cancer, it has provided a basis for genetic counseling of individuals with a family history of pancreatic cancer, and it has established a foundation for prioritizing patients for screening for early pre-invasive disease 21, 29, 31–33. In addition, the discovery of familial pancreatic cancer genes has also lead to the development of gene-specific therapies as demonstrated by the remarkable sensitivity of pancreatic cancers harboring mutations in the BRCA2 gene to Poly[ADP-ribose] polymerase (PARP) inhibitors and to mitomycin C 34–41.
The field of familial pancreatic cancer is getting even more exciting as we enter the era of whole genome sequencing. For example, this year the PALB2 gene was discovered to be a familial pancreatic cancer susceptibility gene through complete, unbiased, sequencing of all of the protein-coding genes in a single patient’s cancer 42, 43. As the speed of “next generation” sequencing technologies rises and the costs fall, we can foresee the discovery of a number of new familial pancreatic cancer genes in the coming years.
The known genetic syndromes account for less than 20% of the observed familial aggregation of pancreatic cancer, and the discovery of additional familial pancreatic cancer genes remains one of the most exciting opportunities in pancreatic cancer research 1, 2. As these genes are discovered, the challenge will be to use these scientific breakthroughs to improve clinical care.