A Metabolomic Signature of Obesity and Risk of Colorectal Cancer: Two Nested Case–Control Studies

Abstract

Obesity is a leading contributor to colorectal cancer (CRC) risk, but the metabolic mechanisms linking obesity to CRC are not fully understood. We leveraged untargeted metabolomics data from two 1:1 matched, nested case–control studies for CRC, including 223 pairs from the US Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial and 190 pairs from a prospective Chinese cohort. We explored serum metabolites related to body mass index (BMI), constructed a metabolomic signature of obesity, and examined the association between the signature and CRC risk. In total, 72 of 278 named metabolites were correlated with BMI after multiple testing corrections (p FDR < 0.05). The metabolomic signature was calculated by including 39 metabolites that were independently associated with BMI. There was a linear positive association between the signature and CRC risk in both cohorts (p for linear < 0.05). Per 1-SD increment of the signature was associated with 38% (95% CI: 9–75%) and 28% (95% CI: 2–62%) higher risks of CRC in the US and Chinese cohorts, respectively. In conclusion, we identified a metabolomic signature for obesity and demonstrated the association between the signature and CRC risk. The findings offer new insights into the underlying mechanisms of CRC, which is critical for improved CRC prevention.

Circulating metabolome landscape in Lynch syndrome

“…The circulating metabolome is associated with cancer risk [ 5 , 8 , 9 ]. Germline mutations in DNA repair genes elevate cancer risk by imposing a high mutation load on fast-proliferating epithelial tissues.…”

“…The circulating metabolome reflects whole-body metabolic processes, which are influenced by genes, lifestyle factors, and health status [ 4 – 7 ]. Based on findings that adiposity-linked circulating metabolite signature is associated with elevated CRC risk [ 8 ], while a metabolite profile reflecting a healthy lifestyle is associated with lower CRC risk [ 5 , 9 ] circulating metabolome holds the potential for characterizing a phenotype susceptible to CRC development.…”

“…Compelling evidence suggests that some circulating metabolites are causally related to cancer development. Lipids and amino acids were the most abundant circulating metabolites associated with CRC risk [ 5 , 8 – 10 ]. Elevated levels of triglycerides, phospholipids, and cholesterol may promote cancer cell growth and proliferation by serving as an energy source and inhibiting CD8 + T cell proliferation [ 11 ].…”

Age‐related cholesterol and colorectal cancer progression: Validating squalene epoxidase for high‐risk cases

“…Numerous studies have reported the association between obesity and CRC (Mandic et al, 2023;Yang et al, 2023;Ye et al, 2020). SQLE, which is the first oxygen-requiring enzyme involved in cholesterol biosynthesis, is upregulated during hypoxic conditions in premalignant formation (Coates et al, 2023).…”

Adiposity and cancer: meta-analysis, mechanisms, and future perspectives

“…In studies to date, adiposity signatures were not shown to substantially mediate the obesitycancer associations for advanced prostate cancer 167 or breast cancer 168 . There was 12% mediation for endometrial cancer 169 and results were mixed for colorectal cancer 169,170 . This relative lack of mediation, when compared with studies of "classical mediators", may reflect low statistical power or that adiposity signatures are not sufficiently specific measures of the key metabolites.…”