Abstract
Pancreatic neuroendocrine tumors (PNETs) are heterogeneous neoplasms which represent only 2% of all pancreatic neoplasms by incidence, but 10% by prevalence. Genetic risk factors could have an important role in the disease aetiology, however only a small number of case control studies have been performed yet. To further our knowledge, we genotyped 13 SNPs belonging to the pleiotropic CDKN2A/B gene region in 320 PNET cases and 4436 controls, the largest study on the disease so far. We observed a statistically significant association between the homozygotes for the minor allele of the rs2518719 SNP and an increased risk of developing PNET (ORhom = 2.08, 95% CI 1.05–4.11, p = 0.035). This SNP is in linkage disequilibrium with another polymorphic variant associated with increased risk of several cancer types. In silico analysis suggested that the SNP could alter the sequence recognized by the Neuron-Restrictive Silencer Factor (NRSF), whose deregulation has been associated with the development of several tumors. The mechanistic link between the allele and the disease has not been completely clarified yet but the epidemiologic evidences that link the DNA region to increased cancer risk are convincing. In conclusion, our results suggest rs2518719 as a pleiotropic CDKN2A variant associated with the risk of developing PNETs.
Highlights
Region Germany Greece Northern Italy Central Italy Southern Italy Poland Total Sex Male Female Median age
To further our understanding on the topic we conducted the largest study on the disease, with up to 320 cases and 4,436 controls, taking advantage of the mainframe of the Pancreatic Disease Research (PANDoRA) Consortium
Rs2518719 is in tight LD with another variant in the gene, rs3731217 (r2 = 0.925, D’ = 1 in Caucasian, as reported by 1000 Genomes), that lies in the first intron of the gene
Summary
Region Germany Greece Northern Italy Central Italy Southern Italy Poland Total Sex Male Female Median age (interquartile range). Genetic polymorphisms in the locus have been reported to be associated with type two diabetes mellitus (T2DM), which is a one of the few suggested risk factors for PNETs14–16, suggesting a shared genetic background between T2DM and PNETs. Genetic variants belonging to the CDKN2A/2B region have been identified through GWAS as susceptibility markers for several human traits and diseases, including a large number of tumor types[17,18,19,20,21,22,23,24]. In a manuscript investigating the genetic susceptibility to endocrine tumors (NETs) Ter-Minassian and colleagues have suggested the association of four SNPs (representing two independent signals because of high linkage disequilibrium (LD)) in this region and an increased risk of the disease[11]. Our hypothesis was that common genetic variability at the locus could modulate the risk of developing PNETs, as it has been shown for other cancer types
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