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Cancer Sci. 2019 Apr 10. doi: 10.1111/cas.14017. [Epub ahead of print]

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

Yang W1,2, Liu H3,4, Duan B3,4, Xu X3,4, Carmody D3,4, Luo S5, Walsh KM3,6, Abbruzzese JL3,7, Zhang X3,8, Chen X2, Wei Q3,4,7.

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Key Laboratory of Fertility Preservation and Maintenance, School of Basic Medicine and the General Hospital, Ningxia Medical University, Yinchuan, 750004, China.
Cancer Research Program, Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC, 27707, USA.
Duke Cancer Institute, Duke University Medical Center, Durham, NC, 27710, USA.
Department of Population Health Sciences, Duke University School of Medicine, Durham, NC, 27710, USA.
Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC, 27710, USA.
Department of Neurosurgery, Duke University School of Medicine, Durham, NC, 27710, USA.
Department of Medicine, Population Health Sciences, Duke University School of Medicine, Durham, NC, 27710.
Department of Pathology, Duke University School of Medicine, Durham, NC, 27710, USA.


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 SNPs in 164 NRF2-related genes and PanC risk using three published genome-wide association study (GWAS) datasets, which included 8,474 cases and 6,944 controls of European descent. We also performed the expression quantitative trait loci (eQTL) analysis to assess the genotype-phenotype correlation of the identified significant SNPs using publicly available data in the 1000 Genomes Project. We found that three novel SNPs (i.e., 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). A combined analysis using the number of unfavorable genotypes (NUGs) of these three SNPs suggested that carriers of 2-3 NUGs had an increased risk of PanC (P < 0.0001), compared with those carrying 0-1 NUGs. Furthermore, the eQTL analysis revealed that both rs3124761 T and the 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. This article is protected by copyright. All rights reserved.


NRF2; genome-wide association study; pancreatic cancer susceptibility; pathway analysis; single nucleotide polymorphism

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