CDKN2A Germline Mutations in Familial Pancreatic Cancer

In Germany about 11,000 patients develop ductal pancreatic adenocarcinoma each year, making it the fifth most common cause of cancer death. 1 The prognosis is dismal, with an overall 5-year survival rate of less than 5%; only 20% of patients have potentially curative resectable tumors at diagnosis. However, in patients with early-stage tumors, 5-year survival rates of up to 40% can be achieved. 2 Thus, the identification of patients at risk for this disease is an important goal to reduce mortality. It has been estimated that about 3% to 10% of patients with pancreatic cancer have an inherited predisposition for this tumor, although conclusive epidemiologic data are still lacking. 3–5 Based on clinical criteria, patients with inherited pancreatic cancer can be separated in two groups. 6,7 One group includes families with an accumulation of PC only (familial pancreatic cancer [FPC]). The underlying gene defect in these families is unknown. The other group consists of families with inherited tumor syndromes or diseases predisposing them to various degrees to pancreatic cancer. These syndromes include hereditary pancreatitis, 8 Peutz-Jeghers syndrome, 9 ataxia-teleangiectasia, 10 hereditary nonpolyposis colon cancer (HNPCC or Lynch II-syndrome 11), Li-Fraumeni syndrome, 12 Gardner syndrome, 13 hereditary breast and ovarian cancer, 14 and familial atypical multiple mole melanoma (FAMMM). 15 The cumulative risk for the development of pancreatic cancer until the age of 70 years in these syndromes varies between 3% and 40%. The CDKNA gene localized at chromosome 9p21 encodes the cyclin-dependent kinase inhibitor p16INK4a (MTS1) and the p53 activator p14ARF. Both gene products have an independent first exon (exon 1-alpha and exon 1-beta, respectively) but share exons 2 and 3 and are translated in different reading frames. The genes are involved in the negative control of cell proliferation. p16INK4a produces a G1 cell-cycle arrest by inhibiting phosphorylation of the retinoblastoma protein, and p14ARF acts both at G1/S and G2/M phases in a p53-dependent manner via binding and inhibition of the protein MDM2. 16,17 p16INK4 is inactivated in 95% of sporadic pancreatic cancers, 18 indicating its important role in the tumorigenesis of this disease. It has also been shown that p16INK4a germline mutations contribute to the familial accumulation of pancreatic cancer and melanoma. In 1995 Whelan et al 19 identified a p16INK4a germline mutation in a family with an excess of pancreatic cancer and malignant melanoma. FAMMM is an autosomal dominant inherited disorder associated with p16INK4a germline mutations; it predisposes mutation carriers to multiple atypical nevi and multiple malignant melanomas. In some FAMMM kindreds a high prevalence of pancreatic cancer has been observed. Goldstein et al 20 suggested dividing FAMMM kindreds in two groups with respect to their mutation status of the p16INK4a tumor suppressor gene: p16INK4a mutation negative kindreds, without the occurrence of pancreatic cancer, and p16INK4a mutation positive kindreds, with a significant excess of pancreatic cancer. It was estimated that p16INK4a mutation-associated FAMMM family members have an 22-fold risk for the development of pancreatic cancer. 20 Moreover, Moskaluk et al recently identified a p16INK4a germline mutation in a family having two first-degree relatives with pancreatic cancer, not showing the FAMMM phenotype. 21 Recently, a germline CDKN2a mutation involving p14ARF was identified in an individual with multiple primary melanomas, 22 but the incidence of p14ARF germline mutations in FPC is not known. Due to the few available data, the role of p16INK4a and p14ARF mutations in the setting of FPC is still not well defined. Therefore, we analyzed FPC families and families with an accumulation of pancreatic cancer and malignant melanoma from the German National Case Collection for Familial Pancreatic Cancer of the Deutsche Krebshilfe (FaPaCa) for the presence of CDKN2A germline mutations including p16INK4a and p14ARF.