CDKN2A germline mutations in familial pancreatic cancer

Objective: To evaluate the prevalence of mutations in the CDKN2A gene encoding p16^INK4a and p14^ARF in familial pancreatic cancer (FPC). Summary Background Data: The genetic basis of FPC is still widely unknown. Recently, it has been shown that germline mutations in the p16^INK4a tumor suppressor gene can predispose to pancreatic cancer. The presence of p14^ARF germline mutations has yet not been determined in this setting. Methods: Eighteen families with at least two first-degree relatives with histologically confirmed pancreatic cancer and five families with at least one patient with pancreatic cancer and another first-degree relative with malignant melanoma of the German National Case Collection for Familial Pancreatic Cancer were analyzed for CDKN2A germline mutations including p16^INK4a and p14^ARF by direct DNA sequencing. All participating family members were genetically counseled and evaluated by a three-generation pedigree. Results None of 18 FPC families without malignant melanoma revealed p16^INK4a mutations, compared to 2 of 5 families with pancreatic cancer and melanoma. Truncating p16^INK4a germline mutations Q50X and E119X were identified in the affected patients of pancreatic cancer plus melanoma families. None of the 23 families revealed p14^ARF germline mutations. Conclusions: CDKN2A germline mutations are rare in FPC families. However, these data provide further evidence for a pancreatic cancer-melanoma syndrome associated with CDKN2A germline mutations affecting p16^INK4a. Thus, all members of families with combined occurrence of pancreatic cancer and melanoma should be counseled and offered screening for p16^INK4a mutations to identify high-risk family members who should be enrolled in a clinical screening program.