title: Cigarette smoking and colorectal cancer risk by KRAS mutation status among older women.
abstract: OBJECTIVE
  Existing data support a modest association between cigarette smoking and incident colorectal cancer (CRC) overall. In this study, we evaluated associations between cigarette smoking and CRC risk stratified by KRAS mutation status, using data and tissue resources from the Iowa Women's Health Study (IWHS).
  
  
  METHODS
  The IWHS is a population-based cohort study of cancer incidence among 41,836 randomly selected Iowa women, ages 55-69 years of age at enrollment (1986). Exposure data, including cigarette smoking, were obtained by self-report at baseline. Incident CRCs (n=1,233) were ascertained by annual linkage with the Iowa Cancer Registry. Archived tissue specimens from CRC cases recorded through 2002 were recently requested for molecular epidemiology investigations. Tumor KRAS mutation status was determined by direct sequencing of exon 2, with informative results in 507/555 (91%) available CRC cases (342 mutation negative and 165 mutation positive). Multivariate Cox regression models were fit to estimate relative risks (RRs) and 95% confidence intervals (CIs) for associations between cigarette smoking variables and KRAS-defined CRC subtypes.
  
  
  RESULTS
  Multiple smoking variables were associated with increased risk for KRAS mutation-negative tumors, including age at initiation (P=0.02), average number of cigarettes per day (P=0.01), cumulative pack-years (P=0.05), and induction period (P=0.04), with the highest point estimate observed for women who smoked ≥40 cigarettes per day on average (RR=2.38; 95% CI=1.25-4.51; compared with never smokers). Further consideration of CRC subsite suggested that cigarette smoking may be a stronger risk factor for KRAS mutation-negative tumors located in the proximal colon than in the distal colorectum. None of the smoking variables were significantly associated with KRAS mutation-positive CRCs (overall or stratified by anatomic subsite).
  
  
  CONCLUSIONS
  Data from this prospective study of older women demonstrate differential associations between cigarette smoking and CRC subtypes defined by KRAS mutation status, and are consistent with the hypothesis that smoking adversely affects the serrated pathway of colorectal carcinogenesis.
authors.affiliation: Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: N J
authors.initials: NJ
authors.lastname: Samadder
authors.forename: Robert A
authors.initials: RA
authors.lastname: Vierkant
authors.forename: Lori S
authors.initials: LS
authors.lastname: Tillmans
authors.forename: Alice H
authors.initials: AH
authors.lastname: Wang
authors.forename: Charles F
authors.initials: CF
authors.lastname: Lynch
authors.forename: Kristin E
authors.initials: KE
authors.lastname: Anderson
authors.forename: Amy J
authors.initials: AJ
authors.lastname: French
authors.forename: Robert W
authors.initials: RW
authors.lastname: Haile
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Harnack
authors.forename: John D
authors.initials: JD
authors.lastname: Potter
authors.forename: Susan L
authors.initials: SL
authors.lastname: Slager
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Smyrk
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
authors.forename: James R
authors.initials: JR
authors.lastname: Cerhan
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Limburg
mesh_terms: D000368:Aged; D015179:Colorectal Neoplasms / Q000209:etiology* / Q000235:genetics*; D005260:Female; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D012306:Risk; D012907:Smoking / Q000009:adverse effects*; D018631:ras Proteins / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins