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

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Date
2019-06
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
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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.
Type
Journal article
Subject
Humans
Pancreatic Neoplasms
Genetic Predisposition to Disease
Risk Factors
Signal Transduction
Gene Frequency
Genotype
Polymorphism, Single Nucleotide
Alleles
Quantitative Trait Loci
NF-E2-Related Factor 2
Genome-Wide Association Study
Permalink
https://hdl.handle.net/10161/19157
Published Version (Please cite this version)
10.1111/cas.14017
Publication Info
Yang, Wenjun; Liu, Hongliang; Duan, Bensong; Xu, Xinyuan; Carmody, Dennis; Luo, Sheng; ... Wei, Qingyi (2019). Three novel genetic variants in NRF2 signaling pathway genes are associated with pancreatic cancer risk. Cancer science, 110(6). pp. 2022-2032. 10.1111/cas.14017. Retrieved from https://hdl.handle.net/10161/19157.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

Abbruzzese

James Abbruzzese

D. C. I. Distinguished Professor of Medical Oncology
My research interests include the clinical study and treatment of pancreatic cancer.
Luo

Sheng Luo

Professor of Biostatistics & Bioinformatics
Walsh

Kyle Walsh

Associate Professor in Neurosurgery
Dr. Walsh is Associate Professor of Neurosurgery and Pathology, Director of the Division of Neuro-epidemiology, and a Senior Fellow in the Duke Center for the Study of Aging and Human Development. He leads Duke’s Neuro-epidemiology Lab, which integrates bench science with statistical methods to study the neurobiology of glial senescence and gliomagenesis. This research interrogates human genomic and epigenomic profiles to identify both heritable and modifiable factors that contribute to ne
Wei

Qingyi Wei

Professor in Population Health Sciences
Qingyi Wei, MD, PhD, Professor in the Department of Medicine, is Associate Director for Cancer Control and Population Sciences, Co-leader of CCPS and Co-leader of Epidemiology and Population Genomics (Focus Area 1). He is a professor of Medicine and an internationally recognized epidemiologist focused on the molecular and genetic epidemiology of head and neck cancers, lung cancer, and melanoma. His research focuses on biomarkers and genetic determinants for the DNA repair deficient phenotype and
Zhang

Xuefeng Zhang

Adjunct Associate Professor in the Department of Pathology
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