Polymorphic variants within non-coding RNA and risk of pancreatic ductal adenocarcinoma

Purpose: Genome-wide association studies found that several polymorphisms affecting risk of pancreatic ductal adenocarcinoma (PDAC) are located in non-coding RNA (ncRNA). The majority of ncRNA are long non-coding RNAs (lncRNA) that are involved in biological processes such as cell growth, differentiation and proliferation. Several recent evidences also point to their role in cancer development and progression. Considering that lncRNA are highly polymorphic and that their expression has been associated with the development of cancer in several organs, including the pancreas, the purpose of this study was to test whether single nucleotide polymorphisms (SNPs) in lncRNA could affect the risk of developing PDAC. Materials and methods: In the human genome, there are 10,205,295 SNPs located in lncRNA (lincSNPs). To test their possible association with PDAC risk we used a two-phase approach: the first phase was conducted in 14,270 individuals (7,207 cases and 7,063 controls) pertaining to the Pancreatic Cancer cohort consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). The 5 lncSNPs with the lowest P-values of association with PDAC risk were genotyped in an additional group of 6,275 individuals, (3,062 PDAC patients and 3,213 controls) in the context of PANcreatic Disease ReseArch (PANDoRA) consortium. Results: In the first phase, we found 37 SNPs associated with PDAC risk with P<10-5. We replicated the best 5, and we observed that one was significant also in the second phase of the study. The T allele of rs7046076 was associated with an increased risk of developing PDAC with OR=1.13 (95%C.I. 1.09-1.18, P=0.003) in the PANDoRA population. A metanalysis of the two phases showed a genome-wide significant association: OR=1.13 (95%C.I. 1.09-1.18, P=1.28x10-8). The T allele disrupts the binding of the lncRNA (NONHSAT133783.2) with a miRNA (hsa-mir-1256) that regulates several genes involved in the cell cycle, such as CDKN2A. Conclusions: We propose a novel PDAC risk locus that lies in a lncRNA that could affect the risk of the disease through the de-regulation of lncRNA-miRNA interactions.