title: A prospective study of duration of smoking cessation and colorectal cancer risk by epigenetics-related tumor classification.
abstract: The effect of duration of cigarette smoking cessation on colorectal cancer risk by molecular subtypes remains unclear. Using duplication-method Cox proportional-hazards regression analyses, we examined associations between duration of smoking cessation and colorectal cancer risk according to status of CpG island methylator phenotype (CIMP), microsatellite instability, v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutation, or DNA methyltransferase-3B (DNMT3B) expression. Follow-up of 134,204 individuals in 2 US nationwide prospective cohorts (Nurses' Health Study (1980-2008) and Health Professionals Follow-up Study (1986-2008)) resulted in 1,260 incident rectal and colon cancers with available molecular data. Compared with current smoking, 10-19, 20-39, and ≥40 years of smoking cessation were associated with a lower risk of CIMP-high colorectal cancer, with multivariate hazard ratios (95% confidence intervals) of 0.53 (0.29, 0.95), 0.52 (0.32, 0.85), and 0.50 (0.27, 0.94), respectively (Ptrend = 0.001), but not with the risk of CIMP-low/CIMP-negative cancer (Ptrend = 0.25) (Pheterogeneity = 0.02, between CIMP-high and CIMP-low/CIMP-negative cancer risks). Differential associations between smoking cessation and cancer risks by microsatellite instability (Pheterogeneity = 0.02), DNMT3B expression (Pheterogeneity = 0.03), and BRAF (Pheterogeneity = 0.10) status appeared to be driven by the associations of CIMP-high cancer with microsatellite instability-high, DNMT3B-positive, and BRAF-mutated cancers. These molecular pathological epidemiology data suggest a protective effect of smoking cessation on a DNA methylation-related carcinogenesis pathway leading to CIMP-high colorectal cancer.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Epidemiology, Harvard School of Public Health, 450 Brookline Avenue, Room JF-215C, Boston, MA 02215, USA.
authors.forename: Reiko
authors.initials: R
authors.lastname: Nishihara
authors.forename: Teppei
authors.initials: T
authors.lastname: Morikawa
authors.forename: Aya
authors.initials: A
authors.lastname: Kuchiba
authors.forename: Paul
authors.initials: P
authors.lastname: Lochhead
authors.forename: Mai
authors.initials: M
authors.lastname: Yamauchi
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Liao
authors.forename: Yu
authors.initials: Y
authors.lastname: Imamura
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Nosho
authors.forename: Kaori
authors.initials: K
authors.lastname: Shima
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kawachi
authors.forename: Zhi Rong
authors.initials: ZR
authors.lastname: Qian
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Chan
authors.forename: Edward
authors.initials: E
authors.lastname: Giovannucci
authors.forename: Shuji
authors.initials: S
authors.lastname: Ogino
mesh_terms: D000368:Aged; D015179:Colorectal Neoplasms / Q000453:epidemiology* / Q000209:etiology / Q000235:genetics; D018899:CpG Islands / Q000235:genetics; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D010641:Phenotype; D016016:Proportional Hazards Models; D011446:Prospective Studies; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D012307:Risk Factors; D012737:Sex Factors; D012907:Smoking / Q000009:adverse effects; D016540:Smoking Cessation / Q000706:statistics & numerical data*; D013997:Time Factors; D000097584:DNA Methyltransferase 3B
chemical_list: D004248:DNA (Cytosine-5-)-Methyltransferases; D048493:Proto-Oncogene Proteins B-raf; D000097584:DNA Methyltransferase 3B; C482119:BRAF protein, human
keywords: carcinogen; carcinoma; epigenomics; hypermethylation; molecular epidemiology; public health; tobacco; translational epidemiology