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

• Published in: Cancer science Vol. 110; no. 6; pp. 2022 - 2032
• Main Authors: Yang, Wenjun, Liu, Hongliang, Duan, Bensong, Xu, Xinyuan, Carmody, Dennis, Luo, Sheng, Walsh, Kyle M., Abbruzzese, James L., Zhang, Xuefeng, Chen, Xiaoxin, Wei, Qingyi
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01-06-2019; John Wiley and Sons Inc
• Subjects: Alcohol; Alleles; Carcinogenesis; Consortia; Datasets; Epidemiology; Gene expression; Gene Frequency; Genes; Genetic diversity; Genetic Predisposition to Disease - genetics; Genome-wide association studies; Genome-Wide Association Study; Genomes; Genotype; Humans; Medical prognosis; Medical research; Metastases; Molecular modelling; NF-E2-Related Factor 2 - genetics; NRF2; Original; Pancreatic cancer; pancreatic cancer susceptibility; Pancreatic Neoplasms - genetics; pathway analysis; Phenotypes; Polymorphism, Single Nucleotide; Quality control; Quantitative trait loci; Quantitative Trait Loci - genetics; Risk Factors; Signal transduction; Signal Transduction - genetics; Single-nucleotide polymorphism; Studies; United States > US; NRF2; pathway analysis; pancreatic cancer susceptibility; single nucleotide polymorphism; genome-wide association study
• ISSN: 1347-9032; 1349-7006; 1349-7006
• DOI: 10.1111/cas.14017

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.
The present study identified three novel SNP in the NRF2 pathway significantly associated with pancreatic cancer risk using a pathway‐based approach to leverage the published pancreatic cancer GWAS datasets and performed additional in silico analysis for their functional relevance.