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.
Type
Journal articleSubject
HumansPancreatic 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
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https://hdl.handle.net/10161/19157Published Version (Please cite this version)
10.1111/cas.14017Publication 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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Show full item recordScholars@Duke
James Abbruzzese
D. C. I. Distinguished Professor of Medical Oncology
My research interests include the clinical study and treatment of pancreatic cancer.
Sheng Luo
Professor of Biostatistics & Bioinformatics
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
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
Xuefeng Zhang
Adjunct Associate Professor in the Department of Pathology
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