Association of Methylation Signatures at Hepatocellular Carcinoma Pathway Genes with Adiposity and Insulin Resistance Phenotypes

• Published in: Nutrition and cancer Vol. 71; no. 5; pp. 840 - 851
• Main Authors: Ramos-Lopez, Omar, Riezu-Boj, Jose I., Milagro, Fermin I., Alfredo Martinez, J.
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 04.07.2019; Taylor & Francis Ltd
• Subjects: Adipose tissue; Adiposity; adults; AKT1 protein; Anthropometry; Associations; Biological activity; Body mass; body mass index; Carcinoma, Hepatocellular - blood; Carcinoma, Hepatocellular - complications; Carcinoma, Hepatocellular - physiopathology; Cell proliferation; CpG islands; Cyclin-dependent kinase 4; data analysis; Deoxyribonucleic acid; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); DNA; DNA damage; DNA methylation; DNA Methylation - physiology; DNA microarrays; Female; Gadd45A protein; Gene expression; Genes; Health risks; Hepatocellular carcinoma; hepatoma; Humans; Insulin; Insulin resistance; Insulin Resistance - physiology; Leukocytes; Liver cancer; Liver Neoplasms - blood; Liver Neoplasms - complications; Liver Neoplasms - physiopathology; LRP5 protein; Male; Metabolism; microarray technology; Middle Aged; Myc protein; Obesity; Obesity - blood; Obesity - complications; Obesity - physiopathology; phenotype; Phenotypes; Risk analysis; Risk factors; Signatures; TOR protein; waist circumference; Wnt protein
• ISSN: 0163-5581; 1532-7914; 1532-7914
• DOI: 10.1080/01635581.2018.1531136

Obesity and type 2 diabetes mellitus are independent risk factors for the onset and progression of hepatocellular carcinoma (HCC). This study aimed to analyze the association of DNA methylation signatures at HCC pathway genes with obesity and related metabolic disturbances. A population of 474 adults within the Methyl Epigenome Network Association (MENA) project was included. DNA methylation levels were measured in white blood cells by microarray. The identification and discrimination of HCC pathway genes were performed using KEGG and PathDIP databases. Anthropometry measurements, the blood metabolic profile, and clinical data were analyzed. The methylation patterns of 20 CpG sites at HCC pathway genes strongly correlated with BMI (FDR <0.0001). These genes encompassed GADD45A, MTOR, FRAT2, E2F3, WNT7B, FRAT1, LRP5, DPF3, GSTA2, APC, MYC, WNT10B, ARID1B, AKT1, GSTA1, WNT5A, CDK4, GAB1, TCF7, which statistically contributed to the regulation of the HCC pathway (P = 2.10e-07). The main biological process where these genes were implicated included uncontrolled cell proliferation, DNA damage, increased survival, and altered oncogenic expression. Interestingly, 9 out of 20 BMI-associated CpGs also correlated with waist circumference and HOMA-IR index. In conclusion, pathway analysis revealed potential associations of DNA methylation signatures at HCC pathway genes with adiposity and insulin resistance phenotypes.