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.
Highlights
The p16-Leiden founder mutation in the Cyclin-dependent kinase inhibitor 2A (CDKN2A) gene is the most common cause of Familial Atypical Multiple Mole Melanoma (FAMMM) syndrome in the Netherlands
All p16-Leiden germline mutation carriers diagnosed at the Laboratory for Diagnostic Genome Analysis (LDGA) between the initiation of CDKN2A gene diagnostics at the LDGA in 1998 and January 1st 2014 were eligible for inclusion
Patient characteristics (Table 1) In total, 422 p16-Leiden germline mutation carriers were eligible for inclusion
Summary
The 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. There is a notable interfamilial variabil‐ ity in the occurrence of pancreatic cancer among p16-Leiden families. In the Netherlands, a founder mutation in the CDKN2A gene, a 19-base pair deletion called p16-Leiden (c.225_243del; RefSeq NM_000077.4), is the most common cause of Familial Atypical Multiple Mole Melanoma (FAMMM) syndrome [2]. There is a notable interfamilial variability in the occurrence of pancreatic cancer among p16-Leiden families [3]. By identifying additional genetic risk factors (genetic modifiers) in these individuals, surveillance could possibly be more individualized
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