Pancreatic cancer-associated gene polymorphisms in a nation-wide cohort of p16-Leiden germline mutation carriers; a case–control study

Abstract

BackgroundThe p16-Leiden founder mutation in the CDKN2A gene is the most common cause of Familial Atypical Multiple Mole Melanoma (FAMMM) syndrome in the Netherlands. Individuals with this mutation are at increased risk for developing melanoma of the skin, as well as pancreatic cancer. However, there is a notable interfamilial variability in the occurrence of pancreatic cancer among p16-Leiden families. We aimed to test whether previously identified genetic risk factors for pancreatic cancer modify the risk for pancreatic cancer in p16-Leiden germline mutation carriers.MethodsSeven pancreatic cancer-associated SNPs were selected from the literature and were genotyped in a cohort of 185 p16-Leiden germline mutation carriers from 88 families, including 50 cases (median age 55 years) with pancreatic cancer and 135 controls (median age 64 years) without pancreatic cancer. Allelic odds ratios per SNP were calculated.ResultsNo significant association with pancreatic cancer was found for any of the seven SNPs.ConclusionsSince genetic modifiers for developing melanoma have already been identified in CDKN2A mutation carriers, this study does not exclude that genetic modifiers do not play a role in the individual pancreatic cancer risk in this cohort of p16-Leiden germline mutation carriers. The search for these modifiers should therefore continue, because they can potentially facilitate more targeted pancreatic surveillance programs.

Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium

“…Most pancreatic surveillance programmes lower the age at which surveillance is initiated for individuals with a first-degree relative with young-onset pancreatic cancer (age <50) 49. For mutation carriers, with a deleterious germline variant, the recommended age to initiate surveillance is generally age 50 ( BRCA2, ATM, PALB2 ), though some groups would start surveillance at age 45 and earlier still for the higher-risk genes; surveillance from age 40 is recommended for CDKN2A mutation carriers; 16% of p16-Leiden mutation carriers with pancreatic cancer were diagnosed at age <4550 and at age 30–40 for those with Peutz-Jegher syndrome 3. When to initiate pancreatic surveillance for these mutation carriers did not reach consensus (online supplementary table S2).…”

Assessing a single SNP located at TERT/CLPTM1L multi-cancer risk region as a genetic modifier for risk of pancreatic cancer and melanoma in Dutch CDKN2A mutation carriers

“…Similarly, cases of melanoma were p16-Leiden carriers who were diagnosed with cutaneous (multiple) melanoma. Detailed medical record data on the study population has been reported previously [12]. Approval of this study was obtained from the ethics committee of Leiden University Medical Center (LUMC #P14.148) [12].…”

“…In an attempt to identify genetic factors that modulate the risk of pancreatic cancer in p16-Leiden carriers, Potjer et al analyzed seven SNPs associated with PC risk in the general population in this cohort of carriers and found no significant association [12]. Recently a risk variant, rs36115365-C, was identified to be significantly correlated with PC risk in the European population [13].…”

Cutaneous malignant melanoma and Parkinson disease: Common pathways?

“…51 Several studies have shown that PARK2 is also a putative tumor suppressor gene, harboring inactivating mutations in many cancer types including renal cell carcinoma, glioblastoma, and colon, lung, and pancreatic cancers. 53,54 A recent study showed that germline inactivating PARK2 mutations are more frequent in CMM cases than in CMM-free controls (OR 5 3.95, 95% CI 5 1. 53,54 A recent study showed that germline inactivating PARK2 mutations are more frequent in CMM cases than in CMM-free controls (OR 5 3.95, 95% CI 5 1.…”

“…42,43,52 Interestingly, pancreatic cancer and nervous system tumors are associated with inherited predisposition to CMM. 53,54 A recent study showed that germline inactivating PARK2 mutations are more frequent in CMM cases than in CMM-free controls (OR 5 3.95, 95% CI 5 1. 34-15.75).…”