David A Drew1,2, Reiko Nishihara3,4,5,6, Paul Lochhead1,2, Aya Kuchiba7, Zhi Rong Qian6, Kosuke Mima6, Katsuhiko Nosho8, Kana Wu4, Molin Wang3,5,9, Edward Giovannucci3,4,9, Charles S Fuchs6,9, Andrew T Chan1,2,9,10, Shuji Ogino3,6,11. 1. Clinical & Translational Epidemiology Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. 2. Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. 3. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA. 4. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA. 5. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA. 6. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. 7. Biostatistics Division, Center for Research Administration and Support, National Cancer Center, Tokyo, Japan. 8. Department of Gastroenterology, Rheumatology, and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan. 9. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. 10. Broad Institute, Cambridge, Massachusetts, USA. 11. Division of MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Abstract
OBJECTIVES: Cigarette smoking has been linked to somatic genetic and epigenetic aberrations, including CpG island methylator phenotype (CIMP)-high, microsatellite instability (MSI)-high and BRAF mutation. These molecular features have been associated with synchronous primary colorectal cancers (CRCs). Thus, we examined the hypothesis that smoking might be associated with the risk of synchronous CRCs. METHODS: Within the Health Professionals Follow-up Study and Nurses' Health Study, we examined the relationship of smoking and incidence of CRC according to tumor synchronicity, using duplication-method Cox proportional hazards regression analysis. RESULTS: We confirmed 1,981 solitary CRC and 45 synchronous CRC cases during follow-up of 134,305 individuals. CRC risk associated with smoking differed significantly by tumor synchronicity status (Pheterogeneity<0.001). When comparing current smokers with never smokers, multivariable hazard ratios (HR) were 5.27 (95% confidence interval (CI), 2.08-13.40) for synchronous CRCs and 0.97 (95% CI, 0.83-1.14) for solitary CRC. Similarly, differential associations were observed when examining cumulative pack-years smoked (Pheterogeneity=0.006). Smoking cessation for ≥10 years relative to current smoking might reduce the risk of synchronous CRCs (multivariable HR=0.42; 95% CI, 0.19-0.95), but not solitary CRC (multivariable HR=1.10; 95% CI, 0.94-1.29; Pheterogeneity=0.001). Comparing current and former smokers with never smokers, multivariable HRs for synchronous CRCs were significantly higher than those of solitary CRC positive for either CIMP-high, MSI-high, or BRAF mutation (Pheterogeneity=0.002). CONCLUSIONS: Smoking is associated with an elevated risk of synchronous CRCs. Our data support a model where smoking contributes to an etiologic field effect that favors these somatic molecular alterations and the development of multiple primary tumors.
OBJECTIVES: Cigarette smoking has been linked to somatic genetic and epigenetic aberrations, including CpG island methylator phenotype (CIMP)-high, microsatellite instability (MSI)-high and BRAF mutation. These molecular features have been associated with synchronous primary colorectal cancers (CRCs). Thus, we examined the hypothesis that smoking might be associated with the risk of synchronous CRCs. METHODS: Within the Health Professionals Follow-up Study and Nurses' Health Study, we examined the relationship of smoking and incidence of CRC according to tumor synchronicity, using duplication-method Cox proportional hazards regression analysis. RESULTS: We confirmed 1,981 solitary CRC and 45 synchronous CRC cases during follow-up of 134,305 individuals. CRC risk associated with smoking differed significantly by tumor synchronicity status (Pheterogeneity<0.001). When comparing current smokers with never smokers, multivariable hazard ratios (HR) were 5.27 (95% confidence interval (CI), 2.08-13.40) for synchronous CRCs and 0.97 (95% CI, 0.83-1.14) for solitary CRC. Similarly, differential associations were observed when examining cumulative pack-years smoked (Pheterogeneity=0.006). Smoking cessation for ≥10 years relative to current smoking might reduce the risk of synchronous CRCs (multivariable HR=0.42; 95% CI, 0.19-0.95), but not solitary CRC (multivariable HR=1.10; 95% CI, 0.94-1.29; Pheterogeneity=0.001). Comparing current and former smokers with never smokers, multivariable HRs for synchronous CRCs were significantly higher than those of solitary CRC positive for either CIMP-high, MSI-high, or BRAF mutation (Pheterogeneity=0.002). CONCLUSIONS: Smoking is associated with an elevated risk of synchronous CRCs. Our data support a model where smoking contributes to an etiologic field effect that favors these somatic molecular alterations and the development of multiple primary tumors.
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