Genetic variants in the liver kinase B1-AMP-activated protein kinase pathway genes and pancreatic cancer risk.
Abstract
The liver kinase B1-AMP-activated protein kinase (LKB1-AMPK) pathway has been identified
as a new target for cancer therapy, because it controls the glucose and lipid metabolism
in response to alterations in nutrients and intracellular energy levels. In the present
study, we aimed to identify genetic variants of the LKB1-AMPK pathway genes and their
associations with pancreatic cancer (PanC) risk using 15 418 participants of European
ancestry from two previously published PanC genome-wide association studies. We found
that six novel tagging single-nucleotide polymorphisms (SNPs) (i.e, MAP2 rs35075084
T > deletion, PRKAG2 rs2727572 C > T and rs34852782 A > deletion, TP53 rs9895829 A > G,
and RPTOR rs62068300 G > A and rs3751936 G > C) were significantly associated with
an increased PanC risk. The multivariate logistic regression model incorporating the
number of unfavorable genotypes (NUGs) with adjustment for age and sex showed that
carriers with five to six NUGs had an increased PanC risk (odds ratio = 1.24, 95%
confidence interval = 1.16-1.32 and P < 0.0001), compared to those with zero to four
NUGs. Subsequent expression quantitative trait loci (eQTL) analysis further revealed
that these SNPs were associated with significantly altered mRNA expression levels
either in 373 normal lymphoblastoid cell lines (TP53 SNP rs9895829, P < 0.05) or in
whole blood cells of 369 normal donors from the genotype-tissue expression project
(GTEx) database [RPTOR SNP rs60268947 and rs28434589, both in high linkage disequilibrium
(r2 > 0.9) withRPTOR rs62068300, P < 0.001]. Collectively, our findings suggest that
these novel SNPs in the LKB1-AMPK pathway genes may modify susceptibility to PanC,
possibly by influencing gene expression.
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https://hdl.handle.net/10161/18472Published Version (Please cite this version)
10.1002/mc.23018Publication Info
Xu, Xinyuan; Qian, Danwen; Liu, Hongliang; Cruz, Diana; Luo, Sheng; Walsh, Kyle M;
... Wei, Qingyi (2019). Genetic variants in the liver kinase B1-AMP-activated protein kinase pathway genes
and pancreatic cancer risk. Molecular carcinogenesis. 10.1002/mc.23018. Retrieved from https://hdl.handle.net/10161/18472.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 of 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
Xuefeng Zhang
Adjunct Associate Professor in the Department of Pathology
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