Abstract
The CDKN2A (p16) gene plays a key role in pancreatic cancer etiology. It is one of the most commonly somatically mutated genes in pancreatic cancer, rare germline mutations have been found to be associated with increased risk of developing familiar pancreatic cancer and CDKN2A promoter hyper-methylation has been suggested to play a critical role both in pancreatic cancer onset and prognosis. In addition several unrelated SNPs in the 9p21.3 region, that includes the CDNK2A, CDNK2B and the CDNK2B-AS1 genes, are associated with the development of cancer in various organs. However, association between the common genetic variability in this region and pancreatic cancer risk is not clearly understood. We sought to fill this gap in a case-control study genotyping 13 single nucleotide polymorphisms (SNPs) in 2,857 pancreatic ductal adenocarcinoma (PDAC) patients and 6,111 controls in the context of the Pancreatic Disease Research (PANDoRA) consortium. We found that the A allele of the rs3217992 SNP was associated with an increased pancreatic cancer risk (ORhet=1.14, 95% CI 1.01-1.27, p=0.026, ORhom=1.30, 95% CI 1.12-1.51, p=0.00049). This pleiotropic variant is reported to be a mir-SNP that, by changing the binding site of one or more miRNAs, could influence the normal cell cycle progression and in turn increase PDAC risk. In conclusion, we observed a novel association in a pleiotropic region that has been found to be of key relevance in the susceptibility to various types of cancer and diabetes suggesting that the CDKN2A/B locus could represent a genetic link between diabetes and pancreatic cancer risk.
Highlights
The majority of pancreatic cancer patients die within a year of diagnosis [1]
We sought to fill this gap in a case-control study genotyping 13 single nucleotide polymorphisms (SNPs) in the context of the PANcreatic Disease ReseArch (PANDoRA) consortium
For the Japanese cases it was not possible to correctly genotype rs3731246 and this SNP was not used in the risk analysis for the Japanese population
Summary
The majority of pancreatic cancer patients die within a year of diagnosis [1]. The poor prognosis is caused by various factors, including the lack of appropriate markers for early detection, the aggressiveness of the disease and the dearth of effective treatment possibilities available. One of the best strategies to reduce the mortality of the disease is to improve early diagnosis, and it is, important to identify individuals at high risk in the population and subject them to enhanced surveillance. Even less is known about the genetic contribution to the disease, since only a rather small number of susceptibility loci have been identified through genomewide association studies (GWAS) [4,5,6,7,8,9] and confirmed by follow-up studies [10]. It has been shown that a small proportion of pancreatic tumors arises as a result of high penetrance germline mutations in genes such as BRCA1, BRCA2, p16/CDKN2A, STK11/LKB, ATM, PALB2, and DNA mismatch repair genes, usually in the context of familial cancer syndromes [2, 3, 11,12,13,14,15]. The very low frequency of those mutations cannot explain the bulk of genetic susceptibility to pancreatic cancer
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