CDKN2A germline mutations in familial pancreatic cancer

Abstract

Objective: To evaluate the prevalence of mutations in the CDKN2A gene encoding p16 and p14 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 tumor suppressor gene can predispose to pancreatic cancer. The presence of p14 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 and p14 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 mutations, compared to 2 of 5 families with pancreatic cancer and melanoma. Truncating p16 germline mutations Q50X and E119X were identified in the affected patients of pancreatic cancer plus melanoma families. None of the 23 families revealed p14 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. Thus, all members of families with combined occurrence of pancreatic cancer and melanoma should be counseled and offered screening for p16 mutations to identify high-risk family members who should be enrolled in a clinical screening program.

Figure 1. Pedigree of PCMS family 25-2-4 with CDKN2A germline mutation E119X. dg., age at diagnosis (years); d., age at death, *, p16^INK4a mutation carrier.

Figure 2. CDKN2A/p16^INK4a germline frameshift mutation c.323-324insG, E119X in affected patients of PCMS family 25-2-4. The insertion of guanine is indicated by an arrow. WT, wild-type; II2, index patient with pancreatic cancer.

Figure 3. Pedigree of PCMS family 22-5-0256 with CDKN2A germline mutation Q50X. dg., age at diagnosis (years); d., age at death, *, p16^INK4a mutation carrier.

Figure 4. CDKN2A/p16^INK4a germline nonsense mutation c.188 C>T, Q50X in affected patients of PCMS family 27-5-0256. The base change from cytosine to thymidine is indicated by an arrow. WT, wild-type sequence.