title: Polymorphisms in the transforming growth factor beta 1 pathway in relation to colorectal cancer progression.
abstract: Transforming growth factor beta1 (TGFB1) acts as a growth inhibitor of normal colonic epithelial cells, however, as a tumor promoter of colorectal cancer (CRC) cells. To explore the association between genetic polymorphisms in the TGFB1 pathway and CRC susceptibility and clinical outcome, we carried out a case-control study on a Swedish population of 308 CRC cases and 585 age- and gender-matched controls. The cases were sampled prospectively and had up to 16 years follow-up, making the study material particularly suitable for survival analysis. On the basis of their reported or predicted functional effect, nine single-nucleotide polymorphisms (TGFB1: Leu10Pro; TGFBR1: 9A/6A and IVS7G+24A; FURIN: C-229T; THBS1: T+42C; LTBP1L: C-256G; LTBP4: T-893G and Thr750Ala; BAMBI: T-779A) were selected for genotyping. We evaluated the associations between genotypes and CRC and Dukes' stage. Survival probabilities were compared between different subgroups. The observed statistically significant associations included a decreased CRC risk for TGFBR1 IVS7G+24A minor allele carriers (odds ratio (OR): 0.72, 95% confidence interval (CI): 0.53-0.97), less aggressive tumors with Dukes' stage A+B for carriers of LTBP4 Thr750Ala and BAMBI T-779A minor alleles (OR: 0.58, 95%CI: 0.36-0.93 and OR: 0.51, 95%CI: 0.29-0.89, respectively) and worse survival for FURIN C-229T heterozygotes (hazard ratio: 1.63, 95%CI: 1.08-2.46). As this is the first study about the influence of the polymorphisms in the TGFB1 pathway on CRC progression, further studies in large independent cohorts are warranted.
authors.affiliation: Department of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany. a.foersti@dkfz.de
authors.forename: Asta
authors.initials: A
authors.lastname: Försti
authors.forename: Xuchen
authors.initials: X
authors.lastname: Li
authors.forename: Kerstin
authors.initials: K
authors.lastname: Wagner
authors.forename: Björn
authors.initials: B
authors.lastname: Tavelin
authors.forename: Kerstin
authors.initials: K
authors.lastname: Enquist
authors.forename: Richard
authors.initials: R
authors.lastname: Palmqvist
authors.forename: Andrea
authors.initials: A
authors.lastname: Altieri
authors.forename: Göran
authors.initials: G
authors.lastname: Hallmans
authors.forename: Kari
authors.initials: K
authors.lastname: Hemminki
authors.forename: Per
authors.initials: P
authors.lastname: Lenner
mesh_terms: D000328:Adult; D000368:Aged; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D018450:Disease Progression; D005091:Exons / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D012004:Rectal Neoplasms / Q000235:genetics / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000235:genetics*
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human