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Genetic variants in the liver kinase B1-AMP-activated protein kinase pathway genes and pancreatic cancer risk.

Publication ,  Journal Article
Xu, X; Qian, D; Liu, H; Cruz, D; Luo, S; Walsh, KM; Abbruzzese, JL; Zhang, X; Wei, Q
Published in: Mol Carcinog
August 2019

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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Published In

Mol Carcinog

DOI

EISSN

1098-2744

Publication Date

August 2019

Volume

58

Issue

8

Start / End Page

1338 / 1348

Location

United States

Related Subject Headings

  • Tumor Suppressor Protein p53
  • Risk
  • Regulatory-Associated Protein of mTOR
  • Quantitative Trait Loci
  • Protein Serine-Threonine Kinases
  • Polymorphism, Single Nucleotide
  • Pancreatic Neoplasms
  • Pancreas
  • Oncology & Carcinogenesis
  • Middle Aged
 

Citation

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Xu, X., Qian, D., Liu, H., Cruz, D., Luo, S., Walsh, K. M., … Wei, Q. (2019). Genetic variants in the liver kinase B1-AMP-activated protein kinase pathway genes and pancreatic cancer risk. Mol Carcinog, 58(8), 1338–1348. https://doi.org/10.1002/mc.23018
Xu, Xinyuan, Danwen Qian, Hongliang Liu, Diana Cruz, Sheng Luo, Kyle M. Walsh, James L. Abbruzzese, Xuefeng Zhang, and Qingyi Wei. “Genetic variants in the liver kinase B1-AMP-activated protein kinase pathway genes and pancreatic cancer risk.Mol Carcinog 58, no. 8 (August 2019): 1338–48. https://doi.org/10.1002/mc.23018.
Xu X, Qian D, Liu H, Cruz D, Luo S, Walsh KM, et al. Genetic variants in the liver kinase B1-AMP-activated protein kinase pathway genes and pancreatic cancer risk. Mol Carcinog. 2019 Aug;58(8):1338–48.
Xu, Xinyuan, et al. “Genetic variants in the liver kinase B1-AMP-activated protein kinase pathway genes and pancreatic cancer risk.Mol Carcinog, vol. 58, no. 8, Aug. 2019, pp. 1338–48. Pubmed, doi:10.1002/mc.23018.
Xu X, Qian D, Liu H, Cruz D, Luo S, Walsh KM, Abbruzzese JL, Zhang X, Wei Q. Genetic variants in the liver kinase B1-AMP-activated protein kinase pathway genes and pancreatic cancer risk. Mol Carcinog. 2019 Aug;58(8):1338–1348.
Journal cover image

Published In

Mol Carcinog

DOI

EISSN

1098-2744

Publication Date

August 2019

Volume

58

Issue

8

Start / End Page

1338 / 1348

Location

United States

Related Subject Headings

  • Tumor Suppressor Protein p53
  • Risk
  • Regulatory-Associated Protein of mTOR
  • Quantitative Trait Loci
  • Protein Serine-Threonine Kinases
  • Polymorphism, Single Nucleotide
  • Pancreatic Neoplasms
  • Pancreas
  • Oncology & Carcinogenesis
  • Middle Aged