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. doi: 10.1002/mc.23018. Epub 2019 Apr 17.


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.

Keywords: genome-wide association study; pancreatic cancer risk; single-nucleotide polymorphism (SNP).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinase Kinases
  • AMP-Activated Protein Kinases / genetics*
  • AMP-Activated Protein Kinases / metabolism
  • Aged
  • Carcinogenesis / genetics
  • Case-Control Studies
  • Cell Line, Tumor
  • Female
  • Genetic Predisposition to Disease / genetics*
  • Genome-Wide Association Study
  • Humans
  • Male
  • Microtubule-Associated Proteins / genetics
  • Middle Aged
  • Pancreas / pathology
  • Pancreatic Neoplasms / genetics*
  • Polymorphism, Single Nucleotide / genetics
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / metabolism
  • Quantitative Trait Loci / genetics
  • Regulatory-Associated Protein of mTOR / genetics
  • Risk
  • Tumor Suppressor Protein p53 / genetics


  • MAP2 protein, human
  • Microtubule-Associated Proteins
  • RPTOR protein, human
  • Regulatory-Associated Protein of mTOR
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • PRKAG2 protein, human
  • Protein Serine-Threonine Kinases
  • STK11 protein, human
  • AMP-Activated Protein Kinase Kinases
  • AMP-Activated Protein Kinases