New Research Examines Role of Serum Metabolites in Colon Cancer Risk Assessment

A multinational research group examined the connections between colon cancer risk and lifestyle factors, measured as the Healthy Lifestyle Index (HLI), compiling and analyzing data from a nested case–control study in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. In addition, the team leveraged untargeted metabolomics data for deriving metabolic signatures of the HLI and its components, as well as evaluated how sex and socioeconomic position (SEP) modulate the relationships between lifestyle, metabolomic profiles, and colon cancer risk. Serum samples studied were analyzed using liquid chromatography-mass spectrometry (LC-MS).A paper based on this research was published in Cancer & Metabolism (1).

A major global health concern, ranking fourth most common cancer in incidence and fifth in mortality worldwide, the diversity of colon cancer incidence rates across geographical regions suggests the involvement of lifestyle factors in its causation (2,3). A review conducted by the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) reported evidence connecting negative lifestyle factors, including physical inactivity, body fat, and poor dietary habits, to an increased risk of developing colorectal cancers; conversely, other research has found that improvements in lifestyle behaviors have been linked to a decreased risk of same (4,5).

Although the influence of lifestyle on colon cancer is well-documented, the fundamental biological mechanisms remain inadequately understood. Metabolomics, the large-scale study of small molecules in biological samples such as blood, has become a valuable tool in the exploration of these metabolic pathways. Prior research published in the EPIC study has recognized metabolic biomarkers connected to the consumption of alcohol and an increased risk of pancreatic and liver cancer, healthy lifestyle and hepatocellular carcinoma, and body size and colorectal cancer, which were more strongly associated with the outcome than the exposure itself (6 –8). This information suggested to the researchers involved with the study discussed that metabolomics may offer the potential for a more thorough understanding of the underlying biological pathways in the relationship of lifestyle and colon cancer development, thus inspiring their research (1).

EPIC is an ongoing multi-center prospective cohort study that, while designed to investigate the relationship between nutrition and cancer, offers the potential for studying other diseases as well. The study currently includes over 500,000 participants (366,521 women and 153,457 men, mostly 35-70 years of age, as of 2002) in 10 European countries, to be followed for cancer incidence and cause-specific mortality for several decades (9,10).

Serum untargeted metabolomics data were acquired using an ultrahigh-pressure liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) system, and reversed phase chromatography and electrospray ionization were employed in both positive and negative polarities. Samples were analyzed in five analytical batches, each consisting of five 96-well plates. Samples were randomized across the batches, with the case–control pairs analyzed next to each other (1).

The researchers found that the HLI score was inversely associated with colon cancer risk, with an odds ratio (OR) per 1-standard deviation (SD) increment equal to 0.79; 95% CI: 0.71, 0.87. The metabolic signature of HLI, comprising 130 features, was moderately correlated with HLI, and was inversely associated with colon cancer risk. After adjustment for the HLI score, the association of the metabolic signature of HLI and colon cancer risk was null. Links between lifestyle factors and the metabolic signature with colon cancer risk were regularly stronger for men than for women and did not differ by SEP (1).

These findings led to the researchers determining that a healthy lifestyle was inversely associated with colon cancer risk, with stronger associations in men than women and no differences across SEP. However, the serum metabolic signatures after adjustment for lifestyle factors were not found to be associated with colon cancer risk. This suggests that lifestyle impacts colon cancer through mechanisms not captured by the signatures (1).

According to the researchers, their work has several strengths. It was the first to apply a weighted, data-driven method of calculating the HLI, a method developed to reduce the bias associated with composite scores, to improve the predictive power of the HLI score, and to provide more accurate estimates of the relationship between lifestyle and disease risk (11). Also, in addition to analyzing the adherence to a healthy lifestyle, their efforts also included component-specific analyses to better examine the role of each lifestyle factor on the risk of colon cancer (1).

However, the researchers admit to their study also having limitations. First, analysts relied on untargeted metabolic data acquired in blood samples collected at recruitment, the same time as lifestyle exposure assessment. Therefore, while the researchers presumed that lifestyle-related behaviors drove changes in metabolic profiles, this temporal relationship cannot be definitively established in the study because of the simultaneous assessment of lifestyle data and blood collection. Additionally, their analysis of SEP may have been limited by using the highest education level attained to its measurement. While education is a well-established proxy for SEP in epidemiological studies, there are other indicators, such as occupation, income, and parental education, which may provide information to more accurately characterize participants' SEP, as well as aid in the investigation of its complex relationship with lifestyle factors and disease risk (1).

3D rendered Medical Illustration of Male Anatomy with Colon Cancer. © Kaulitzki - stock.adobe.com

References

1. Matta, K.; Viallon, V.; Chatziioannou, A. C. et al. Can Serum Metabolic Signatures Inform on the Relationship Between Healthy Lifestyle and Colon Cancer Risk? Cancer Metab. 2025, 13 (1), 30. DOI: 10.1186/s40170-025-00388-0
2. 2. Ferlay, J.; Ervik, M.; Laversanne, M. et al. Global Cancer Observatory: Cancer Today. https://gco.iarc.who.int/today/ (accessed 2024-02-20)
3. Murphy, N.; Moreno, V.; Hughes, D. J. et al. Lifestyle and Dietary Environmental Factors in Colorectal Cancer Susceptibility. Mol. Aspects. Med. 2019, 69, 2-9.DOI: 10.1016/j.mam.2019.06.005
4. Vieira, A. R.; Abar, L.; Chan, D. S. M. et al. Foods and Beverages and Colorectal Cancer Risk: A Systematic Review and Meta-Analysis of Cohort Studies, An update of the Evidence of the WCRF-AICR Continuous Update Project. Ann. Oncol. 2017, 28 (8), 1788-1802. DOI: 10.1093/annonc/mdx171
5. Botteri, E.; Peveri, G.; Berstad, P. et al. Changes in Lifestyle and Risk of Colorectal Cancer in the European Prospective Investigation into Cancer and Nutrition. Am. J. Gastroenterol. 2023, 118 (4), 702-711. DOI: 10.14309/ajg.0000000000002065
6. Loftfield, E.; Stepien, M.; Viallon, V. et al. Novel Biomarkers of Habitual Alcohol Intake and Associations with Risk of Pancreatic and Liver Cancers and Liver Disease Mortality. J. Natl. Cancer Inst. 2021, 113 (11), 1542-1550. DOI: 10.1093/jnci/djab078
7. Assi, N.; Gunter, M. J.; Thomas, D. C. et al. Metabolic Signature of Healthy Lifestyle and its Relation with Risk of Hepatocellular Carcinoma in a Large European Cohort. Am. J. Clin. Nutr. 2018, 108 (1), 117-126. DOI: 10.1093/ajcn/nqy074
8. Kliemann, N.; Viallon, V.; Murphy, N. et al. Metabolic Signatures of Greater Body Size and their Associations with Risk of Colorectal and Endometrial Cancers in the European Prospective Investigation into Cancer and Nutrition. BMC Med. 2021, 19 (1), 101. DOI: 10.1186/s12916-021-01970-1
9. Riboli, E.; Hunt, K. J.; Slimani, N. et al.European Prospective Investigation into Cancer and Nutrition (EPIC): Study Populations and Data Collection. Public Health Nutr. 2002, 5 (6B), 1113-1124. DOI: 10.1079/PHN2002394
10. EPIC-Europe Study. https://epic.iarc.fr/ (accessed 2025-06-19)
11. Viallon, V.; Freisling, H.; Matta, K. et al. On the Use of the Healthy Lifestyle Index to Investigate Specific Disease Outcomes. Sci. Rep. 2024, 14 (1), 16330. DOI: 10.1038/s41598-024-66772-w