The CIMP-high phenotype is associated with energy metabolism alterations in colon adenocarcinoma

• Published in: BMC medical genetics 2019-04, Vol.20 (Suppl 1), p.52-27, Article 52
• Main Authors: Fedorova, Maria S, Krasnov, George S, Lukyanova, Elena N, Zaretsky, Andrew R, Dmitriev, Alexey A, Melnikova, Nataliya V, Moskalev, Alexey A, Kharitonov, Sergey L, Pudova, Elena A, Guvatova, Zulfiya G, Kobelyatskaya, Anastasiya A, Ishina, Irina A, Slavnova, Elena N, Lipatova, Anastasia V, Chernichenko, Maria A, Sidorov, Dmitry V, Popov, Anatoly Y, Kiseleva, Marina V, Kaprin, Andrey D, Snezhkina, Anastasiya V, Kudryavtseva, Anna V
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Adenocarcinoma - genetics; Adenocarcinoma - metabolism; Aged; Analysis; Apoptosis; Biochemistry; Bioinformatics; Biomarkers; Breast cancer; Cancer genetics; CIMP; Classification; Colon; Colon adenocarcinoma; Colon cancer; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Colorectal cancer; Computational Biology; CpG islands; CpG Islands - genetics; Data processing; Deoxyribonucleic acid; Diagnosis; DNA; DNA Methylation; Energy; Energy metabolism; Energy Metabolism - genetics; Female; Gastrointestinal diseases; Gene expression; Genes; Genetic aspects; Genetic research; Genomes; Genomics; Genotype & phenotype; Gluconeogenesis; Glucose metabolism; Glyceraldehyde-3-phosphate dehydrogenase; Glycolysis; Health aspects; Humans; Kinases; Male; Messenger RNA; Metabolic pathways; Metabolism; Methylation; Middle Aged; Molecular modelling; Mutation; Oncogenes; Phenotype; Phenotypes; Polymerase chain reaction; Promoter Regions, Genetic; Pyruvate kinase; Pyruvic acid; Reproducibility of Results; RNA; RNA sequencing; RNA-Seq; Russia; TCGA; Tricarboxylic acid cycle; Tumors
• ISSN: 1471-2350; 1471-2350
• DOI: 10.1186/s12881-019-0771-5

CpG island methylator phenotype (CIMP) is found in 15-20% of malignant colorectal tumors and is characterized by strong CpG hypermethylation over the genome. The molecular mechanisms of this phenomenon are not still fully understood. The development of CIMP is followed by global gene expression alterations and metabolic changes. In particular, CIMP-low colon adenocarcinoma (COAD), predominantly corresponded to consensus molecular subtype 3 (CMS3, "Metabolic") subgroup according to COAD molecular classification, is associated with elevated expression of genes participating in metabolic pathways. We performed bioinformatics analysis of RNA-Seq data from The Cancer Genome Atlas (TCGA) project for CIMP-high and non-CIMP COAD samples with DESeq2, clusterProfiler, and topGO R packages. Obtained results were validated on a set of fourteen COAD samples with matched morphologically normal tissues using quantitative PCR (qPCR). Upregulation of multiple genes involved in glycolysis and related processes (ENO2, PFKP, HK3, PKM, ENO1, HK2, PGAM1, GAPDH, ALDOA, GPI, TPI1, and HK1) was revealed in CIMP-high tumors compared to non-CIMP ones. Most remarkably, the expression of the PKLR gene, encoding for pyruvate kinase participating in gluconeogenesis, was decreased approximately 20-fold. Up to 8-fold decrease in the expression of OGDHL gene involved in tricarboxylic acid (TCA) cycle was observed in CIMP-high tumors. Using qPCR, we confirmed the increase (4-fold) in the ENO2 expression and decrease (2-fold) in the OGDHL mRNA level on a set of COAD samples. We demonstrated the association between CIMP-high status and the energy metabolism changes at the transcriptomic level in colorectal adenocarcinoma against the background of immune pathway activation. Differential methylation of at least nine CpG sites in OGDHL promoter region as well as decreased OGDHL mRNA level can potentially serve as an additional biomarker of the CIMP-high status in COAD.