Physical activity and molecular subtypes of colorectal cancer: a pooled observational analysis and Mendelian randomization study.

Authors

Chalitsios CV, Markozannes G, Aglago EK, Berndt SI, Buchanan DD, Campbell PT, Cao Y, Chan AT, Dimou N, Drew DA, French AJ, Georgeson P, Giannakis M, Gruber SB, Gunter MJ, Harrison TA, Hoffmeister M, Hsu L, Huang WY, Hullar MAJ, ...show more Huyghe JR, Lynch BM, Moreno V, Murphy N, Newton CC, Nowak JA, Obón-Santacana M, Ogino S, Qu C, Schmit SL, Steinfelder RS, Sun W, Thomas CE, Toland AE, Trinh QM, Ugai T, Um CY, Guelpen BV, Zaidi SH, Schoen RE, Woods MO, Brenner H, Andreson L, Pellatt AJ, Peters U, Phipps AI, Tsilidis KK

Affiliations

• Department of Hygiene and Epidemiology, University of Ioannina, Ioannina, Greece.
• Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
• Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
• Colorectal Oncogenomics Group, Department of Clinical Pathology, Melbourne Medical School, The University of Melbourne, Parkville, Australia.
• Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, United States.
• Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St Louis, MO, United States.
• Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States.
• Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France.
• Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States.
• Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States.

Abstract

BACKGROUND: Physical activity is associated with lower colorectal cancer (CRC) risk, but its association with molecular subtypes defined by genetic and epigenetic alterations of the disease is unclear. Such information may enhance the understanding of the mechanisms related to the benefits of physical activity.

METHODS: Pooled observational (cases: n = 5386; controls: n = 6798; studies n = 5) and genome-wide association data (cases: n = 8178; controls: n = 10 472; studies n = 5) were used. We used multivariable logistic regression models and Mendelian randomization to assess the association between physical activity and the risk of CRC subtypes defined by individual tumor markers (and marker combinations), namely microsatellite instability status, CpG island methylator phenotype status, and BRAF and KRAS mutations. We used case-only analysis to test for differences between molecular subtypes. We applied Bonferroni correction to account for multiple tests.

RESULTS: In the pooled observational analysis, higher levels of physical activity were associated with lower CRC risk (Obs-per 1SD, odds ratio [OR] = 0.94, 95% confidence interval [CI] = 0.90 to 0.97), with an association that was stronger in males (Obs-per 1SD, OR = 0.91, 95% CI = 0.87 to 0.96) than in females (Obs-per 1SD, OR = 0.97, 95% CI = 0.91 to 1.03; Pinteraction = .04). Higher physical activity was associated with a lower risk of CRC across all molecular subtypes, especially in males. There was no difference in the associations by subtypes by pooled observational or Mendelian randomization analyses. The findings did not differ by study design, anatomical site, and early or late age onset of CRC.

CONCLUSIONS: Our findings suggest that physical activity is not differentially associated with the 4 major molecular subtypes involved in colorectal carcinogenesis, indicating that its benefits extend broadly across colorectal cancer pathogenesis.