Three novel genetic variants in NRF2 signaling pathway genes are associated with pancreatic cancer risk

Abstract

Pancreatic cancer (PanC) is one of the most lethal solid malignancies, and metastatic PanC is often present at the time of diagnosis. Although several high‐ and low‐penetrance genes have been implicated in PanC, their roles in carcinogenesis remain only partially elucidated. Because the nuclear factor erythroid2‐related factor2 (NRF2) signaling pathway is involved in human cancers, we hypothesize that genetic variants in NRF2 pathway genes are associated with PanC risk. To test this hypothesis, we assessed associations between 31 583 common single nucleotide polymorphisms (SNP) in 164 NRF2‐related genes and PanC risk using three published genome‐wide association study (GWAS) datasets, which included 8474 cases and 6944 controls of European descent. We also carried out expression quantitative trait loci (eQTL) analysis to assess the genotype‐phenotype correlation of the identified significant SNP using publicly available data in the 1000 Genomes Project. We found that three novel SNP (ie, rs3124761, rs17458086 and rs1630747) were significantly associated with PanC risk ( P = 5.17 × 10 −7 , 5.61 × 10 −4 and 5.52 × 10 −4 , respectively). Combined analysis using the number of unfavorable genotypes (NUG) of these three SNP suggested that carriers of two to three NUG had an increased risk of PanC ( P < 0.0001), compared with those carrying zero to one NUG. Furthermore, eQTL analysis showed that both rs3124761 T and rs17458086 C alleles were associated with increased mRNA expression levels of SLC2A6 and SLC2A13 , respectively ( P < 0.05). In conclusion, genetic variants in NRF2 pathway genes could play a role in susceptibility to PanC, and further functional exploration of the underlying molecular mechanisms is warranted.

Why PRP works only on certain patients with tennis elbow? Is PDGFB gene a key for PRP therapy effectiveness? A prospective cohort study

“…Literature data regarding SNPs are fragmentary and usually come from case-control studies on different phenotypes, mainly cancers. For example, the variants of rs5757572, rs1800817 and rs2247128 SNPs which improved the results of PROMs were previously associated with increased risk of pancreatic cancer,[ 22 ] gall bladder cancer [ 23 ] and breast cancer. [ 24 ] The fact that these variants are risk factors of the neoplastic process, may suggest that they are rather markers of PDGF-dependent proliferative potential of cells, which would partly explain the observed results.…”

Genome‐wide scan of long noncoding RNA single nucleotide polymorphisms and pancreatic cancer susceptibility

“…In addition, several studies have identified body mass index as a causative factor for PDAC development using a Mendelian randomization approach 8‐10 . The genetic susceptibility to PDAC is the result of the involvement of rare high penetrance mutations and high frequency low penetrance variants discovered through genome wide association studies (GWAS) or large multicentric candidate gene approaches 11‐22 …”

“…[8][9][10] The genetic susceptibility to PDAC is the result of the involvement of rare high penetrance mutations and high frequency low penetrance variants discovered through genome wide association studies (GWAS) or large multicentric candidate gene approaches. [11][12][13][14][15][16][17][18][19][20][21][22] The recent advances in the knowledge on the regulatory regions of the human genome have highlighted that several GWAS hits associated with a variety of human traits, including PDAC risk, are located in DNA sequences containing noncoding RNA (ncRNA). 23 The vast majority of ncRNAs consists of long noncoding RNA (lncRNA), and recent evidences suggest that around 68% of the human transcriptome consists of lncRNAs.…”

Associations between pancreatic expression quantitative traits and risk of pancreatic ductal adenocarcinoma

“…Moreover, rare high-penetrance mutations and high-frequency lowpenetrance variants, discovered through genome-wide association studies (GWASs), contribute, alone or in combination, to the genetic susceptibility of PDAC (7)(8)(9)(10)(11)(12)(13)(14)(15). Additional susceptibility variants have been identified through large multicentric gene candidate approaches and through secondary analysis of published GWAS data (16)(17)(18)(19)(20)(21)(22)(23)(24)(25). The number of identified loci is, however, very small if compared with breast, prostate or colorectal cancers and the fraction of the heritability they explain is limited.…”