Abstract 2638: Genetic association analysis of the AMP dependent protein kinase complex and NHL risk
Authors: Hoffman Aaron E. , Demanelis Kathryn C. , Zheng Tongzhang , Zhu Yong 
Published: August 2012

Abstract
Introduction: AMPK regulates metabolic processes by sensing intracellular concentrations of ATP and AMP and has been implicated in at least two important tumor-related pathways: the mTOR pathway and the p53 axis. We utilize a population-based epidemiologic analysis to investigate the role of mutations in seven AMPK subunits and lymphomagenesis and analyze public microarray expression data to determine the expression of AMPK in non-Hodgkin lymphoma (NHL) cells. Methods: Our analysis included incident and histologically confirmed cases of NHL (n=456) and age-matched matched controls (n=527) from female residents of Connecticut. Single nucleotide polymorphisms (SNPs) were identified using the Tagger algorithm in the Haploview interface in HapMap's genome browser 22. A total of 19 SNPs (r2 ≤ 0.8 and MAF ≤ 0.2) were identified across the AMPK subunit genes. For each gene harboring more than one tagging SNP (PRKAA2, PRKAG2, and PRKAG3), haplotypes were estimated using the PHASE program. All statistical analyses were done in SAS 9.2. An unconditional multivariate logistic model was generated and the adjusted odds ratios (ORs) and 95% confidence intervals were reported. Family history of cancer was found to be an effect modifier for some SNPs and haplotypes, and stratified analyses were performed for these associations. We extracted gene expression data from GEO (GDS3516) and compared median AMPK subunit levels in NHL cells to the levels in normal follicle B-cells and total peripheral blood B-cells using a Wilcoxon rank sum test. Results: Individuals with no family history of cancer and heterozygous for rs293445 in the PRKAG1 subunit had a significantly increased risk of NHL (OR: 2.80, 95% CI: 1.54, 5.07; p&lt;0.001). The strongest association was noted for a haplotype in PRKAA2 among individuals who reported no family history of cancer (OR: 5.44, 95% CI: 2.15, 13.75; p&lt;0.001). The median gene expression of PRKAA2 was significantly elevated in follicular lymphoma cells compared to normal follicle B cells (p&lt;0.05). A suggestive association between rare PRKAG3 haplotypes and diffuse large B cell lymphoma (DLCBCL) was noted among individuals with no family history of cancer (OR: 0.36, 95% CI: 0.17, 0.78)), but this association was not significant after correction for multiple comparisons. PRKAG3 was significantly lower (p&lt;0.05) in DLCBCL cells relative to normal peripheral blood B cells, and in follicular lymphoma cells relative to follicle center B cells. Conclusions: These findings suggest that variants in AMPK may influence NHL risk. Our expression analysis demonstrates differential expression of some AMPK subunits in lymphoma tissue relative to normal immune cells. Metabolic dysregulation has been suggested as an “emerging hallmark of cancer,” and future studies may focus on understanding the role of AMPK in tumor metabolism and utilizing this information to develop new strategies for chemotherapy and prevention.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2638. doi:1538-7445.AM2012-2638