Cohort Analysis Reveals Subtype-Specific Effects of Obesity on the Colorectal Tumor Transcriptome

In this study, we investigated the consensus molecular subtype (CMS)-dependent effects of obesity on the colorectal cancer (CRC) tumor transcriptome. Colorectal cancer is the third most common cancer and the third leading cause of cancer-related deaths in the U.S. 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 not been fully elucidated in part because of the molecular heterogeneity of CRC. In 2015, an international consortium classified CRC into four CMSs with distinct characteristics. Yet, it is not known whether the mechanisms linking obesity and colon cancer are molecular subtype specific. Thus, we examined the transcriptomic profile of tumors from obese patients compared to healthy BMI patients. RNA-sequencing data and associated patient body mass index (BMI) data for 231 patients were obtained from The Cancer Genomic Atlas - Colon Adenocarcinoma (TCGA-COAD) Program. Samples were classified into the four CMSs with the CMScaller R package, while calculated BMI was used to categorize patients as normal, overweight, or obese. Gene Set Enrichment Analysis (GSEA) was conducted to compare obese and normal categories within each CMS. Differentially expressed genes (DEGs) were uncovered with the DESeq2 R package.

We observed that cancer-associated inflammatory pathways such as the IL6 JAK/STAT3 and interferon gamma response were enriched in obese samples compared to normal samples in CMS 1, 2, and 4, indicating that obesity can upregulate similar oncogenic pathways in CRC patients with different subtypes. We also found that inflammatory M1 macrophages and cancer-associated fibroblasts were enriched in obese samples compared to normal samples in the immune infiltrated subtype CMS1 and the stromal infiltrated subtype CMS4, respectively, suggesting that obesity can enhance distinct CMS features.

Moreover, when obese and normal patients were compared for each CMS, the obtained DEGs differed between the subtypes, enabling the formation of CMS-specific obesity-associated gene signatures. Further analysis revealed that high expression of these gene signatures was associated with lower patient survival in CRC cohorts.

Overall, our findings suggest that obesity can enhance known oncogenic inflammatory pathways in CRC and has CMS-dependent effects on CRC. Obesity-associated gene signatures were also identified for each CMS and may have prognostic value.