title: TGFBR1 intralocus epistatic interaction as a risk factor for colorectal cancer.
abstract: In colorectal cancer (CRC), an inherited susceptibility risk affects about 35% of patients, whereas high-penetrance germline mutations account for <6% of cases. A considerable proportion of sporadic tumors could be explained by the coinheritance of multiple low-penetrance variants, some of which are common. We assessed the susceptibility to CRC conferred by genetic variants at the TGFBR1 locus. We analyzed 14 polymorphisms and the allele-specific expression (ASE) of TGFBR1 in 1025 individuals from the Spanish population. A case-control study was undertaken with 504 controls and 521 patients with sporadic CRC. Fourteen polymorphisms located at the TGFBR1 locus were genotyped with the iPLEX Gold (MassARRAY-Sequenom) technology. Descriptive analyses of the polymorphisms and haplotypes and association studies were performed with the SNPator workpackage. No relevant associations were detected between individual polymorphisms or haplotypes and the risk of CRC. The TGFBR1*9A/6A polymorphism was used for the ASE analysis. Heterozygous individuals were analyzed for ASE by fragment analysis using cDNA from normal tissue. The relative level of allelic expression was extrapolated from a standard curve. The cutoff value was calculated with Youden's index. ASE was found in 25.4% of patients and 16.4% of controls. Considering both bimodal and continuous types of distribution, no significant differences between the ASE values of patients and controls were identified. Interestingly, a combined analysis of the polymorphisms and ASE for the association with CRC occurrence revealed that ASE-positive individuals carrying one of the most common haplotypes (H2: 20.7%) showed remarkable susceptibility to CRC (RR: 5.25; 95% CI: 2.547-5.250; p<0.001) with a synergy factor of 3.7. In our study, 54.1% of sporadic CRC cases were attributable to the coinheritance of the H2 haplotype and TGFBR1 ASE. These results support the hypothesis that the allelic architecture of cancer genes, rather than individual polymorphisms, more accurately defines the CRC risk.
authors.affiliation: Molecular Genetics Laboratory, Elche University Hospital, Elche, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Martinez-Canto
authors.forename: Adela
authors.initials: A
authors.lastname: Castillejo
authors.forename: Trinidad
authors.initials: T
authors.lastname: Mata-Balaguer
authors.forename: Maria-Isabel
authors.initials: MI
authors.lastname: Castillejo
authors.forename: Eva
authors.initials: E
authors.lastname: Hernandez-Illan
authors.forename: Esperanza
authors.initials: E
authors.lastname: Irles
authors.forename: Victor Manuel
authors.initials: VM
authors.lastname: Barbera
authors.forename: Cecilia
authors.initials: C
authors.lastname: Egoavil
authors.forename: Carla
authors.initials: C
authors.lastname: Guarinos
authors.forename: Cristina
authors.initials: C
authors.lastname: Alenda
authors.forename: Enrique
authors.initials: E
authors.lastname: Ochoa
authors.forename: Rafael
authors.initials: R
authors.lastname: Lazaro
authors.forename: Silvia
authors.initials: S
authors.lastname: Fajardo
authors.forename: Javier
authors.initials: J
authors.lastname: Lacueva
authors.forename: Rafael
authors.initials: R
authors.lastname: Calpena
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Soto
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002277:Carcinoma / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics*; D004843:Epistasis, Genetic / Q000502:physiology*; D005260:Female; D056426:Genetic Loci / Q000235:genetics / Q000502:physiology; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000502:physiology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000502:physiology; D012307:Risk Factors; D055815:Young Adult
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human