Prudence R Carr1, Efrat L Amitay1, Lina Jansen1, Elizabeth Alwers1,2, Wilfried Roth3,4, Esther Herpel4,5, Matthias Kloor6, Martin Schneider7, Hendrik Bläker8, Jenny Chang-Claude9,10, Hermann Brenner1,11,12, Michael Hoffmeister1. 1. Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany. 2. Medical Faculty Heidelberg, University of Heidelberg, Heidelberg, Germany. 3. Institute of Pathology, University Medical Center Mainz, Mainz, Germany. 4. Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany. 5. NCT Tissue Bank, National Center for Tumor Diseases (NCT), Heidelberg, Germany. 6. Department of Applied Tumor Biology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany. 7. Department of Surgery, Heidelberg University Hospital, Heidelberg, Germany. 8. Institute of Pathology, Charité University Medicine, Berlin, Germany. 9. Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany. 10. Genetic Tumor Epidemiology Group, University Medical Center Hamburg-Eppendorf, University Cancer Center Hamburg, Hamburg, Germany. 11. Division of Preventive Oncology, German Cancer Research Center, Heidelberg, Germany. 12. German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany.
Abstract
BACKGROUND: Observational studies have consistently shown that a high BMI is associated with increased risk of colorectal cancer (CRC). However, the underlying mechanisms linking obesity to CRC remain unclear. OBJECTIVES: To investigate the associations of BMI and CRC by major molecular pathological subtypes of CRC. METHODS: This analysis included 2407 cases and 2454 controls from a large German population-based case-control study. Information on recent weight and height as well as other demographic and lifestyle data were obtained by standardized interviews. Multinomial logistic regression was used to estimate ORs and 95% CIs for the associations between BMI and risk of CRC by major molecular pathological features: microsatellite instability (MSI), CpG island methylator phenotype (CIMP), B-Raf proto-oncogene serine/threonine kinase (BRAF) mutation, and Kirsten rat sarcoma viral oncogene homolog gene (KRAS) mutation. RESULTS: Among women, a higher BMI was differentially and more strongly associated with risk of MSI CRC (OR per 5 kg/m2: 1.69; 95% CI: 1.34, 2.12; Pheterogeneity ≤ 0.001), CIMP-high CRC (OR per 5 kg/m2: 1.57; 95% CI: 1.30, 1.89; Pheterogeneity ≤ 0.001), BRAF-mutated CRC (OR per 5 kg/m2: 1.56; 95% CI: 1.22, 1.99; Pheterogeneity = 0.04), and KRAS-wildtype CRC (OR per 5 kg/m2: 1.35; 95% CI: 1.17, 1.54; Pheterogeneity = 0.01), compared with the risk of CRC in subjects with the molecular feature counterpart. In men, no meaningful differences in CRC risk were observed for the investigated molecular feature pairs. For the association of BMI with MSI CRC, we observed effect modification by sex (Pinteraction = 0.04). Also, in women, the risk of CRC with the serrated pathway features was more strongly increased with higher BMI than risk of CRC with the traditional pathway features (OR per 5 kg/m2: 1.73; 95% CI: 1.28, 2.34; Pheterogeneity = 0.01). CONCLUSIONS: In women, the relation between BMI and MSI-high CRC seems to be stronger than that between BMI and microsatellite-stable CRC. However, a validation in an independent cohort is needed. This observational study was registered at the German Clinical Trials Register (http://www.drks.de; study ID: DRKS00011793), an approved primary register in the WHO network.
BACKGROUND: Observational studies have consistently shown that a high BMI is associated with increased risk of colorectal cancer (CRC). However, the underlying mechanisms linking obesity to CRC remain unclear. OBJECTIVES: To investigate the associations of BMI and CRC by major molecular pathological subtypes of CRC. METHODS: This analysis included 2407 cases and 2454 controls from a large German population-based case-control study. Information on recent weight and height as well as other demographic and lifestyle data were obtained by standardized interviews. Multinomial logistic regression was used to estimate ORs and 95% CIs for the associations between BMI and risk of CRC by major molecular pathological features: microsatellite instability (MSI), CpG island methylator phenotype (CIMP), B-Raf proto-oncogene serine/threonine kinase (BRAF) mutation, and Kirsten ratsarcoma viral oncogene homolog gene (KRAS) mutation. RESULTS: Among women, a higher BMI was differentially and more strongly associated with risk of MSI CRC (OR per 5 kg/m2: 1.69; 95% CI: 1.34, 2.12; Pheterogeneity ≤ 0.001), CIMP-high CRC (OR per 5 kg/m2: 1.57; 95% CI: 1.30, 1.89; Pheterogeneity ≤ 0.001), BRAF-mutated CRC (OR per 5 kg/m2: 1.56; 95% CI: 1.22, 1.99; Pheterogeneity = 0.04), and KRAS-wildtype CRC (OR per 5 kg/m2: 1.35; 95% CI: 1.17, 1.54; Pheterogeneity = 0.01), compared with the risk of CRC in subjects with the molecular feature counterpart. In men, no meaningful differences in CRC risk were observed for the investigated molecular feature pairs. For the association of BMI with MSI CRC, we observed effect modification by sex (Pinteraction = 0.04). Also, in women, the risk of CRC with the serrated pathway features was more strongly increased with higher BMI than risk of CRC with the traditional pathway features (OR per 5 kg/m2: 1.73; 95% CI: 1.28, 2.34; Pheterogeneity = 0.01). CONCLUSIONS: In women, the relation between BMI and MSI-high CRC seems to be stronger than that between BMI and microsatellite-stable CRC. However, a validation in an independent cohort is needed. This observational study was registered at the German Clinical Trials Register (http://www.drks.de; study ID: DRKS00011793), an approved primary register in the WHO network.
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