title: The TGFBR1*6A allele is not associated with susceptibility to colorectal cancer in a Spanish population: a case-control study.
abstract: BACKGROUND
  TGF-beta receptor type I is a mediator of growth inhibitory signals. TGFBR1*6A (rs11466445) is a common polymorphic variant of the TGF-beta receptor I gene and has been associated with tumour susceptibility. Nevertheless, the role of this polymorphism as a risk factor for colorectal cancer is controversial. The aim of this study was to assess the association between TGFBR1*6A and colorectal cancer, age, sex, tumour location and tumour stage in a Spanish population.
  
  
  METHODS
  The case-control study involved 800 Spanish subjects: 400 sporadic colorectal cancer patients and 400 age-, sex-, and ethnic-matched controls. The odds ratio (OR) and 95% confidence interval (95% CI) for the TGFBR1*6A polymorphism were calculated using unconditional logistic regression adjusted for age and sex. Analysis of somatic mutations at the GCG repeat of TGFBR1 exon 1 and germline allele-specific expression were also conducted to obtain further information on the contribution of the TGFBR1*6A allele to CRC susceptibility.
  
  
  RESULTS
  There was no statistically significant association between the TGFBR1*6A allele and CRC (p > 0.05). The OR was 1.147 (95% CI: 0.799-1.647) for carriers of the TGFBR1*6A allele and 0.878 (95% CI: 0.306-2.520) for homozygous TGFBR1*6A individuals compared with the reference. The frequency of the polymorphism was not affected by age, sex or tumour stage. The TGFBR1*6A allele was more prevalent among colon tumour patients than among rectal tumour patients. Tumour somatic mutations were found in only two of 69 cases (2.9%). Both cases involved a GCG deletion that changed genotype 9A/9A in normal DNA to genotype 9A/8A. Interestingly, these two tumours were positive for microsatellite instability, suggesting that these mutations originated because of a deficient DNA mismatch repair system.Allele-specific expression of the 9A allele was detected in seven of the 14 heterozygous 9A/6A tumour cases. This could have been caused by linkage disequilibrium of the TGFBR1*6A allele with mutations that cause allele-specific expression, as was recently suggested.
  
  
  CONCLUSIONS
  Our results suggest that the TGFBR1*6A allele does not confer an increased risk of colorectal cancer in the Spanish population.
authors.affiliation: Molecular Oncology Group, Elche University Hospital, Camino Almazara 11, Elche, Spain. acastillejo@umh.es
authors.forename: Adela
authors.initials: A
authors.lastname: Castillejo
authors.forename: Trinidad
authors.initials: T
authors.lastname: Mata-Balaguer
authors.forename: Paola
authors.initials: P
authors.lastname: Montenegro
authors.forename: Enrique
authors.initials: E
authors.lastname: Ochoa
authors.forename: Rafael
authors.initials: R
authors.lastname: Lázaro
authors.forename: Ana
authors.initials: A
authors.lastname: Martínez-Cantó
authors.forename: María-Isabel
authors.initials: MI
authors.lastname: Castillejo
authors.forename: Carla
authors.initials: C
authors.lastname: Guarinos
authors.forename: Víctor-Manuel
authors.initials: VM
authors.lastname: Barberá
authors.forename: Carmen
authors.initials: C
authors.lastname: Guillén-Ponce
authors.forename: Alfredo
authors.initials: A
authors.lastname: Carrato
authors.forename: José-Luís
authors.initials: JL
authors.lastname: Soto
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics*; D005091:Exons; D005260:Female; D016368:Frameshift Mutation; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D013030:Spain
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