Cigarette smoking and colorectal cancer risk by molecularly defined subtypes.
BACKGROUND
Cigarette smoking is an established risk factor for colorectal cancer. Because colorectal carcinogenesis is a heterogeneous process, we investigated whether cigarette smoking is differentially associated with molecularly defined subtypes of colorectal cancer.


METHODS
We evaluated associations between smoking and incident colorectal cancer, overall and by microsatellite instability (MSI) phenotype (MSI-high vs MSI-low or microsatellite stable), CpG island methylator phenotype (CIMP positive or CIMP negative), and BRAF mutation status (BRAF mutation positive or BRAF mutation negative), among 37 399 participants in a population-based cohort study (the Iowa Women's Health Study). Cigarette smoking (and other exposures) was assessed by self-report at baseline in 1986, including smoking status (never and ever [former or current]), age at initiation, total duration, average number of cigarettes smoked per day, cumulative pack-years, and induction period. Vital status and state of residence were determined by mailed follow-up questionnaires in 1987, 1989, 1992, and 1997 and by linkage to Iowa death certificate records. Nonrespondents were checked via the National Death Index to identify descendants. Participants with newly diagnosed (ie, incident) colorectal cancer were identified through annual linkage with the Iowa Cancer Registry. Archived paraffin-embedded tumor tissue specimens were obtained for 555 patients with colorectal cancer who were diagnosed from January 1, 1986, through December 31, 2002, and MSI status, CIMP status, and BRAF status were determined. Multivariable Cox regression models were fit to estimate relative risks (RRs) and 95% confidence intervals (CIs).


RESULTS
Ever-smokers were at moderately increased risk for incident colorectal cancer (RR = 1.19, 95% CI = 1.05 to 1.35) compared with never-smokers. Higher risk estimates were observed for current smokers with MSI-high tumors (RR = 1.99, 95% CI = 1.26 to 3.14), CIMP-positive tumors (RR = 1.88, 95% CI = 1.22 to 2.90), and BRAF mutation-positive tumors (RR = 1.92, 95% CI = 1.22 to 3.02). Other smoking-related variables (ie, age at initiation, total duration, average number of cigarettes smoked per day, cumulative pack-years, and induction period) were also associated with MSI-high, CIMP-positive, and BRAF mutation-positive tumor subtypes. Conversely, cigarette smoking status (ever vs never) was not associated with the MSI-low or microsatellite stable (RR = 1.00, 95% CI = 0.79 to 1.25), CIMP-negative (RR = 1.02, 95% CI = 0.81 to 1.30), or BRAF mutation-negative subtypes (RR = 1.00, 95% CI = 0.65 to 1.27).


CONCLUSIONS
In this prospective study of older women, cigarette smoking was associated with the MSI-high, CIMP-positive, and BRAF mutation-positive colorectal cancer subtypes, which indicates that epigenetic modification may be functionally involved in smoking-related colorectal carcinogenesis.
Limsui
David
D
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA.
Vierkant
Robert A
RA
Tillmans
Lori S
LS
Wang
Alice H
AH
Weisenberger
Daniel J
DJ
Laird
Peter W
PW
Lynch
Charles F
CF
Anderson
Kristin E
KE
French
Amy J
AJ
Haile
Robert W
RW
Harnack
Lisa J
LJ
Potter
John D
JD
Slager
Susan L
SL
Smyrk
Thomas C
TC
Thibodeau
Stephen N
SN
Cerhan
James R
JR
Limburg
Paul J
PJ
D000368:Aged; D015179:Colorectal Neoplasms / Q000453:epidemiology* / Q000209:etiology* / Q000235:genetics; D016001:Confidence Intervals; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D015994:Incidence; D007484:Iowa / Q000453:epidemiology; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation; D016017:Odds Ratio; D010641:Phenotype; D016016:Proportional Hazards Models; D011446:Prospective Studies; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012042:Registries; D018570:Risk Assessment; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects*
D004273:DNA, Neoplasm; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf