Abstract 3037: Effect of obesity on the promoter methylation of regulators of glucose catabolism and its association with prognosis in colorectal cancer

Abstract

Abstract Metabolic alterations due to obesity are involved in the development of colorectal cancer (CRC) and it may mediate epigenetic alterations such as changes in DNA methylation. This research aimed to associate the effect of obesity on both the methylation of promoters of genes regulating glucose catabolism (n=52) and the prognosis of CRC. The study population was composed of 301 CRC patients of the TCGA-COADREAD project whose clinical and epigenomic data were available. Patients were classified by BMI according to the WHO guidelines. Multiple linear regression was used to estimate the relationship between gene expression and promoter methylation status with BMI. Logistic regression models were used to estimate a correlation between gene expression and promoter methylation status with response to primary anticancer treatment. Kaplan Meier plots were used to determine the association between the gene promoter methylation and overall survival (OS). Mean BMI was 25.2 kg/m2 (± 3.8) and, the prevalence of obesity was 29% in the TCGA-COADREAD cohort. Under-expression of ACO2, PGAM1, and TPI1 genes, and over-expression of GCK were found with an increase in BMI. Also, hypermethylation of the ACO2 (OR: 3.62e-57, CI 3.2e-112 - 0.04) and PGAM1 (OR: 1.75e-22, CI 0.04 - 3.8) promoters decreases the probability of complete remission in CRC patients. Only genes HKDC1 and OGDHL resulted differentially methylated between obese and non-obese CRC patients but their expression was not associated with OS (p>0.05). We concluded that an increase in BMI is associated with changes in expression and promoter methylation of a group of glucose catabolism regulators in CRC. Such changes are associated with disease remission in CRC patients (Table 1). Our results may raise awareness about obesity's effects on CRC prognosis. Further research is encouraged on glucose catabolism genes and their methylation levels to confirm and validate such factors as prognostic markers of CRC. GE: Gene expression, PRM: Promoter region methylation. Adjusted by age, BMI, and presence of polyps. Crude model Adjusted model Response to primary treatment OR 95% CI OR 95% CI ACO2 GE 1.53 0.5 - 4.6 1.56 0.4 - 5.8 PRM 8.99e-36 7.6e-86 - 1.1e+11 3.62e-57 3.2e-112 - 0.04 GCK GE 1.52 0.8 - 3 1.24 0.5 - 2.9 PRM 249.8 0.3 - 204182.6 341.4 0.1 - 1209515 HKDC1 GE 1.3 0.8 - 1.9 1.4 0.87 - 2.3 PRM 0.3 0.03 - 2.4 0.38 0.04 - 3.8 OGDHL GE 1.64 1.13 - 2.4 1.93 1.2 - 3.1 PRM 24.99 0.09 - 6903.4 14458.2 0.01 - 1.49e+10 PGAM1 GE 1.17 0.5 - 2.9 1.24 0.4 - 3.7 PRM 2.48e-13 0.03 - 2.4 1.75e-22 0.04 - 3.8 TPI1 GE 1.62 0.5 - 4.9 1.68 0.4 - 6.5 PRM 1.08e-32 4.1e-104 - 2.84e+39 4.01e-73 5.3e-161 - 3.1e+15 Citation Format: Valeria Clara Morales Ancajima, Claudia Inés Machicado Rivero. Effect of obesity on the promoter methylation of regulators of glucose catabolism and its association with prognosis in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3037.