Consensus molecular subtype differences linking colon adenocarcinoma and obesity revealed by a cohort transcriptomic analysis

Abstract

Colorectal cancer (CRC) is the third-leading cause of cancer-related deaths in the United States and worldwide. Obesity—a worldwide public health concern—is a known risk factor for cancer including CRC. However, the mechanisms underlying the link between CRC and obesity have yet to be fully elucidated in part because of the molecular heterogeneity of CRC. We hypothesized that obesity modulates CRC in a consensus molecular subtype (CMS)-dependent manner. RNA-seq data and associated tumor and patient characteristics including body weight and height data for 232 patients were obtained from The Cancer Genomic Atlas–Colon Adenocarcinoma (TCGA-COAD) database. Tumor samples were classified into the four CMSs with the CMScaller R package; body mass index (BMI) was calculated and categorized as normal, overweight, and obese. We observed a significant difference in CMS categorization between BMI categories. Differentially expressed genes (DEGs) between obese and overweight samples and normal samples differed across the CMSs, and associated prognostic analyses indicated that the DEGs had differing associations on survival. Using Gene Set Enrichment Analysis, we found differences in Hallmark gene set enrichment between obese and overweight samples and normal samples across the CMSs. We constructed Protein-Protein Interaction networks and observed differences in obesity-regulated hub genes for each CMS. Finally, we analyzed and found differences in predicted drug sensitivity between obese and overweight samples and normal samples across the CMSs. Our findings support that obesity impacts the CRC tumor transcriptome in a CMS-specific manner. The possible associations reported here are preliminary and will require validation using in vitro and animal models to examine the CMS-dependence of the genes and pathways. Once validated the obesity-linked genes and pathways may represent new therapeutic targets to treat colon cancer in a CMS-dependent manner.

Molecular Mechanisms of Western Diet-Induced Obesity and Obesity-Related Carcinogenesis—A Narrative Review

“…When the consensus molecular subtypes (CMS) were analysed for colorectal cancers in 252 patients from the Cancer Genomic Atlas–Colon Adenocarcinoma (TCGA-COAD) database, obesity-induced enrichment of EMT- and metabolism-related hallmark genes in mesenchymal-type (CMS4) and a greater percentage of metabolic type (CMS3) colorectal cancers were found in obese compared to normal BMI patients [ 33 ]. The transcriptome-based CMS classification includes CRC with varying KRAS mutations (23% in CMS1, 28% in CMS2, 68% in CMS3 and 38% in CMS4) [ 34 ].…”

“…Exposure to exogenous and endogenously formed carcinogens through the consumption of highly processed foods, a high-fat diet, red meat and lack of dietary plant phytochemicals and antioxidants are implicated in carcinogenesis. The consumption of red meat, processed red meat preserved with sodium nitrite/nitrate and meat cooked at high temperature (grilling/frying/charbroiling) which produces nitrosamines, heterocyclic amines or advanced glycation end products is associated with obesity and gastric, kidney, pancreatic and colorectal cancer [ 22 , 33 , 42 , 158 , 159 , 160 ]. Heme from red meat may increase the endogenous generation of N-nitrosamines compared to white meat, and somatic mutations of KRAS and APC associated with CRC [ 154 ].…”

“…A Mediterranean diet contains dietary polyphenols, vitamins and omega-3 fatty acids derived from fish, fruits, nuts, vegetables and wholegrains, which have anti-inflammatory and anti-obesity effects [ 161 ]. A ‘green’ Mediterranean diet has higher amounts of dietary polyphenols which have been correlated with greater loss of VAT, in conjunction with lowered red meat intake and increased dietary fibre [ 33 , 46 , 52 , 159 , 161 ]. Phytochemicals including polyphenols, flavonoids, quinones, saponins and coumarins modulate the Wnt/ β -catenin signalling pathway which inhibits transcription factors involved in adipogenesis such as C/EBPα and PPAR γ , preventing preadipocyte differentiation [ 158 ].…”

Systematic Review and Meta-Analysis of the Impact of Bariatric Surgery on Future Cancer Risk

“…The molecular mechanisms involved in obesity and carcinogenesis are closely related [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ]. These include hyperinsulinemia, elevated leptin, chronic inflammation, oxidative stress, activation of HIF-1α and cytokines, DNA methylation, dysfunctional visceral adipose tissue secretome, adipokine and exosome miRNA release and alterations in the sex hormone metabolism.…”