title: Phenotypic and tumor molecular characterization of colorectal cancer in relation to a susceptibility SMAD7 variant associated with survival.
abstract: The minor allele (G) of rs4939827, a SMAD7 (18q21) intronic variant, is associated with a lower risk of developing colorectal cancer (CRC) and poorer survival after diagnosis. Our objective was to evaluate the associations of this variant with different tumor phenotype and intratumoral molecular characteristics. We evaluated 1509 CRC cases and 2307 age-matched controls nested within the Nurses' Health Study and the Health Professionals Follow-up Study. We used the TaqMan assay to genotype rs4939827 and logistic regression to assess the association of rs4939827 with risk of CRC according to different phenotypic and molecular characteristics. We found that the minor allele (G) in rs4939827 (SMAD7, 18q21) was associated with a lower risk of developing tumor stage pT1 or pT2 CRC [multivariate odds ratio (OR), 0.73; 95% confidence interval (CI) 0.62-0.87] but not tumor stage pT3 or pT4 (multivariate OR, 1.07; 95% CI 0.93-1.23, P for heterogeneity = 1.2 × 10(-4)). The association between rs4939827 and CRC also significantly differed by methylation of RUNX3 (P for heterogeneity = 0.005). Among those with CRC, the minor allele (G) in rs4939827 was significantly associated with poorer overall survival (hazards ratio, 1.20; 95% CI, 1.02-1.42). We can conclude that the minor allele (G) of the germline intronic SMAD7 variant rs4939827 is associated with a lower risk of CRC with earlier tumor stage and CRC without methylation of the tumor suppressor RUNX3. These findings suggest that individuals with this SMAD7 variant that develop CRC are more probably to have tumors with greater invasiveness and methylation of RUNX3, which potentially contributes to their poorer observed survival.
authors.affiliation: Department of Epidemiology, Harvard School of Public Health,  677 Huntington Avenue, Boston, MA 02115, USA.
authors.forename: Xabier
authors.initials: X
authors.lastname: Garcia-Albeniz
authors.forename: Hongmei
authors.initials: H
authors.lastname: Nan
authors.forename: Linda
authors.initials: L
authors.lastname: Valeri
authors.forename: Teppei
authors.initials: T
authors.lastname: Morikawa
authors.forename: Aya
authors.initials: A
authors.lastname: Kuchiba
authors.forename: Amanda I
authors.initials: AI
authors.lastname: Phipps
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Hutter
authors.forename: Ulrike
authors.initials: U
authors.lastname: Peters
authors.forename: Polly A
authors.initials: PA
authors.lastname: Newcomb
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
authors.forename: Edward L
authors.initials: EL
authors.lastname: Giovannucci
authors.forename: Shuji
authors.initials: S
authors.lastname: Ogino
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Chan
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics / Q000401:mortality* / Q000473:pathology; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics*; D004247:DNA / Q000235:genetics; D019175:DNA Methylation; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D009367:Neoplasm Staging; D010641:Phenotype; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D011446:Prospective Studies; D012307:Risk Factors; D051906:Smad7 Protein / Q000235:genetics*; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D050677:Core Binding Factor Alpha 3 Subunit; C493729:Runx3 protein, human; C497806:SMAD7 protein, human; D051906:Smad7 Protein; D004247:DNA