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. 2025 Jun 16;13(1):30.
doi: 10.1186/s40170-025-00388-0.

Can serum metabolic signatures inform on the relationship between healthy lifestyle and colon cancer risk?

Komodo Matta  1 , Vivian Viallon  2 , Anastasia Chrysovalantou Chatziioannou  2 , Nivonirina Robinot  2 , Roland Wedekind  2 , Christina C Dahm  3 , Agnetha Linn Rostgaard-Hansen  4 , Anne Tjønneland  4   5 , Therese Truong  6 , Chloé Marques  6 , Pauline Frenoy  6 , Rudolf Kaaks  7 , Renée Turzanski Fortner  7   8 , Matthias B Schulze  9   10 , Sabrina Sieri  11 , Mario Fordellone  12 , Rosario Tumino  13 , Fulvio Ricceri  14 , Tonje Braaten  15   16 , Therese Haugdahl Nøst  15   17   18 , Maria-Jose Sánchez  19   20   21 , Olatz Mokoroa-Carollo  22   23 , Sandra Colorado-Yohar  21   24   25 , Camino Trobajo-Sanmartín  21   26   27 , Keren Papier  28 , Rhea Harewood  29 , Kostas Tsilidis  30   31 , Salvatore Vaccarella  2 , Mattias Johansson  2 , Elisabete Weiderpass  2 , Cyrille Delpierre  32   33 , Sebastien Lamy  2   32   33 , Kristin Benjaminsen Borch  15 , Pekka Keski-Rahkonen  2 , Elio Riboli  30 , Heinz Freisling  2 , Marc Gunter  2   30 , Pietro Ferrari  2
Affiliations

Can serum metabolic signatures inform on the relationship between healthy lifestyle and colon cancer risk?

Komodo Matta et al. Cancer Metab. .

Abstract

Background: Colon cancer is strongly influenced by lifestyle factors. Sociodemographic factors like sex and socioeconomic position (SEP) might modulate the relationship between lifestyle and colon cancer risk. Metabolomics offers potential to uncover biological mechanisms linking lifestyle and colon cancer.

Methods: Lifestyle and untargeted metabolomic data were available from a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC), including 1,067 colon cancer cases and 1,067 controls matched on age, sex, study centre, and blood collection time. Serum samples were analyzed using liquid chromatography-mass spectrometry. The Healthy Lifestyle Index (HLI) score was derived from smoking habits, alcohol intake, body mass index (BMI), physical activity, and diet. Penalised regression was applied in controls to derive metabolic signatures for the HLI and the lifestyle components. Associations of lifestyle factors and the metabolic signatures with colon cancer risk were estimated in conditional logistic regression models, overall and by sex and SEP.

Results: 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 (r = 0.59; 94% CI: 0.56, 0.61), and was inversely associated with colon cancer risk (OR = 0.86; 95% CI: 0.78, 0.95). After adjustment for the HLI score, the association of the metabolic signature of HLI and colon cancer risk was null (OR = 1.00, 95% CI 0.88, 1.13). Associations of lifestyle factors and the metabolic signature with colon cancer risk were consistently stronger for men than for women and did not differ by SEP.

Conclusions: In this study across seven European countries, 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, suggesting that lifestyle impacts colon cancer through mechanisms not captured by the signatures.

Keywords: Colon cancer; Healthy Lifestyle; LASSO regression; Sex; Socioeconomic position; Untargeted metabolomics.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: The approval of the European Prospective Investigation into Cancer and nutrition (EPIC) cohort by the IARC Ethics Committee (IEC) was initially given in 1995. The EPIC cohort and projects undertaken within the EPIC cohort, were successfully re-evaluated by the IEC in 2017 to support the requirement of ethics approval at the centres’ level, as requested by IARC-EPIC PIs and by the EPIC Steering Committee. Consent for publication: Not applicable. This work does not contain any individual level data. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
ORs (95% CI) for colon cancer risk and the Healthy Lifestyle Index (HLI) and the metabolic signature of HLI (MetSig HLI), overall, by sex and by SEP. All estimates are reported for a 1-standard deviation increase, adjusted for height and educational level, and stratified by the matched case-set. Unadjusted estimates are modelled with either HLI or MetSig HLI and covariates. Adjusted estimates reflect a mutually adjusted model with both HLI and MetSig HLI, and covariates
Fig. 2
Fig. 2
UpSet plot of features selected in the metabolic signatures of the Healthy Lifestyle Index (HLI) and of the lifestyle components and their intersections
Fig. 3
Fig. 3
ORs (95% CI) for colon cancer risk and lifestyle components and their metabolic signatures. All estimates are reported for a 1-standard deviation increase and all models were stratified by match case-set. Unadjusted estimates are modelled with either the lifestyle component or the metabolic signature (MetSig). Adjusted estimates are modelled with the metabolic signature of each respective lifestyle component, adjusted for all five lifestyle components and covariates
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