title: A Prospective Study of Smoking and Risk of Synchronous Colorectal Cancers.
abstract: 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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
authors.affiliation: Clinical & Translational Epidemiology Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Drew
authors.affiliation: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.|Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.|Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Reiko
authors.initials: R
authors.lastname: Nishihara
authors.affiliation: Clinical & Translational Epidemiology Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Lochhead
authors.affiliation: Biostatistics Division, Center for Research Administration and Support, National Cancer Center, Tokyo, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Kuchiba
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Zhi Rong
authors.initials: ZR
authors.lastname: Qian
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Mima
authors.affiliation: Department of Gastroenterology, Rheumatology, and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Nosho
authors.affiliation: Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
authors.forename: Kana
authors.initials: K
authors.lastname: Wu
authors.affiliation: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.|Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.|Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Molin
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.|Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.|Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Giovannucci
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
authors.affiliation: Clinical & Translational Epidemiology Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.|Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Chan
authors.affiliation: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Division of MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Shuji
authors.initials: S
authors.lastname: Ogino
mesh_terms: D000328:Adult; D000368:Aged; D002277:Carcinoma / Q000453:epidemiology* / Q000235:genetics; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000453:epidemiology* / Q000235:genetics; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D009378:Neoplasms, Multiple Primary / Q000453:epidemiology* / Q000235:genetics; D010641:Phenotype; D016016:Proportional Hazards Models; D011446:Prospective Studies; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D012907:Smoking / Q000453:epidemiology*; D016540:Smoking Cessation / Q000706:statistics & numerical data; D013997:Time Factors; D014481:United States / Q000453:epidemiology
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf