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INTERNATIONAL CONGRESS OF

CancerGenetics

• Association Between Metabolic Syndrome and Colorectal Cancer Risk and Mortality: Insights from Epidemiological, Genetic, and Molecular Evidence

• Sara Jomehpour Karizaki,¹ Amir Mohammad Davar Panah,² Mohammad Hossein Pour-akbar,³ Seyed Reza Mirhafez,⁴ Saeedeh Askarian,^5,*
  1. Department of Medical Biotechnology, Neyshabur University of Medical Sciences, Neyshabur, Iran.
  2. Department of Medical Biotechnology, Neyshabur University of Medical Sciences, Neyshabur, Iran.
  3. Department of Medical Biotechnology, Neyshabur University of Medical Sciences, Neyshabur, Iran.
  4. Department of Medical Biotechnology, Neyshabur University of Medical Sciences, Neyshabur, Iran.
  5. Department of Medical Biotechnology, Neyshabur University of Medical Sciences, Neyshabur, Iran.
  
  
  
• Introduction: Colorectal cancer (CRC) remains one of the most common malignancies worldwide, and its increasing burden has been accompanied by a global rise in obesity and metabolic syndrome (MetS). MetS, a cluster of interconnected metabolic abnormalities including central obesity, insulin resistance and hyperglycemia, hypertension, and dyslipidemia, may contribute to colorectal carcinogenesis through multiple overlapping mechanisms. Chronic low-grade inflammation, hyperinsulinemia, insulin-like growth factor signaling, altered adipokine secretion, oxidative stress, and changes in the gut microbiome have all been implicated in this relationship. Importantly, recent advances in genetic epidemiology, Mendelian randomization, and multi-omics research have provided new opportunities to distinguish potentially causal metabolic determinants from conventional epidemiological associations and to identify molecular pathways linking metabolic dysfunction to CRC initiation and progression.
• Methods: A focused review of peer-reviewed literature published between 2018 and 2026 was conducted using PubMed, Scopus, and Web of Science. We reviewed and summarized research assessing the relationship between the incidence, mortality and prognosis of colorectal cancer and MetS and its components. Particular emphasis is placed on Mendelian randomization analyzes, prospective cohort studies, systematic reviews and meta-analyses, and novel data on molecular mechanisms, genetic susceptibility, microbiome changes, and multi-omics approaches. In this study we also investigated the potential relevance of these findings for biomarker discovery, cancer risk and precision prevention.
• Results: the evidence showed a large association between MetS and CRC risk. A systematic review and meta-analysis of 18 studies reported that MetS was associated with a 36% greater risk of CRC overall (RR = 1.36, 95% CI: 1.26–1.47). It observed a comparable association in men (RR = 1.33, 95% CI: 1.21 to 1.47) and women (RR = 1.34, 95% CI: 1.19 to 1.52), with the risk increased according to enhanced number of MetS components. More recent data from a meta-analysis of 31 prospective cohorts confirmed a significant yet more modest link between MetS and CRC risk (RR = 1.13, 95% CI: 1.12–1.15). Notably, the combination of obesity, hypertension and hyperglycemia had the strongest association with CRC risk, and the effect estimates were higher in men (RR=1.54, 95% CI: 1.49–1.61) than in women. Genetic epidemiological evidence further strengthens the biological plausibility of this association. Mendelian randomization analyses have supported potentially causal relationships between genetically predicted adiposity-related traits, including body mass index and waist-to-hip ratio, as well as long-term glycemic exposure reflected by HbA1c, and CRC risk. These findings suggest that specific metabolic disturbances may contribute directly to colorectal carcinogenesis rather than merely representing correlated lifestyle-associated risk factors. MetS also appears to influence CRC prognosis. A systematic review and meta-analysis of CRC patients demonstrated that MetS was associated with increased all-cause mortality (HR = 1.342, 95% CI: 1.107–1.627) and substantially higher CRC-specific mortality (HR = 2.122, 95% CI: 1.080–4.173). CRC-specific mortality increased progressively with the accumulation of metabolic risk factors, reaching an HR of 2.327 (95% CI: 1.262–4.291) among patients presenting with three metabolic abnormalities. Collectively, current evidence suggests that the relationship between MetS and CRC involves a complex interaction among metabolic dysfunction, inflammation, hormonal signaling, host genetic susceptibility, and potentially the gut microbiome and other molecular networks. Emerging multi-omics approaches may help identify metabolomic, transcriptomic, epigenetic, and microbiome-derived biomarkers capable of improving the characterization of high-risk individuals.
• Conclusion: Metabolic syndrome is associated with increased risk of colorectal cancer and worse clinical outcomes, with risk increasing as metabolic abnormalities accumulate. Mendelian randomization studies provide additional support for potentially causal roles of genetically influenced adiposity and glycemic traits in colorectal carcinogenesis. In the future, the integration of metabolic phenotypes with genetic, epigenetic, metabolomic and microbiome data may offer a more holistic framework for CRC risk stratification and early detection. These approaches may allow identification of molecularly distinct high-risk subgroups and support specific prevention strategies and precision oncology interventions. As several metabolic risk factors are modifiable, improving metabolic health may be an important complementary strategy to reduce the global burden of CRC.
• Keywords: Metabolic Syndrome; Colorectal Neoplasms; Obesity; Body Mass Index; Precision Medicine.