title: An intronic variant of the TGFBR1 gene is associated with carcinomas of the kidney and bladder.
abstract: TGF-beta signaling is frequently perturbed in many human cancers, including renal cell carcinomas (RCCs) and transitional cell carcinomas (TCCs) of the bladder. Genetic alterations of the TGF-beta type 1 receptor (TGFBR1) may contribute to these perturbations. We therefore examined variations in the TGFBR1 gene by PCR, SSCP and RFLP in carcinomas of the urinary system and in tissues from noncancer, age-matched controls. A G-->A variant 24 bp downstream of the exon/intron 7 boundary of the TGFBR1 gene (Int7G24A) was evident in patients with RCC (46.5%, n = 86) and bladder and upper urinary tract TCC (49.2%, n = 65) significantly more frequently than in age-matched controls (28.3%, n = 113, p < 0.002 by chi2 test). Moreover, 8 homozygous variant carriers were found in the cancer groups, whereas not a single homozygous variant carrier was found in the control group. The Int7G24A allele (both heterozygous G/A and homozygous A/A carriers) was associated with increased RCC incidence (OR = 2.20, 95% CI 1.22-3.96) and TCC incidence (OR = 2.45, 95% CI 1.89-3.16). One somatic mutation of serine to phenylalanine at codon 57 of the TGFBR1 gene was confirmed in an upper urinary tract TCC. In conclusion, the Int7G24A variant in the TGFBR1 gene is significantly more frequent in patients with RCC and TCC than normal age-matched controls, suggesting that it may represent a risk factor for the development of kidney and bladder carcinomas.
authors.affiliation: Wood Hudson Cancer Research Laboratory, Newport, KY, USA. tchen@woodhudson.org
authors.forename: Taiping
authors.initials: T
authors.lastname: Chen
authors.forename: Chad
authors.initials: C
authors.lastname: Jackson
authors.forename: Ben
authors.initials: B
authors.lastname: Costello
authors.forename: Natalie
authors.initials: N
authors.lastname: Singer
authors.forename: Bruce
authors.initials: B
authors.lastname: Colligan
authors.forename: Larry
authors.initials: L
authors.lastname: Douglass
authors.forename: Jackson
authors.initials: J
authors.lastname: Pemberton
authors.forename: James
authors.initials: J
authors.lastname: Deddens
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Graff
authors.forename: Julia H
authors.initials: JH
authors.lastname: Carter
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002292:Carcinoma, Renal Cell / Q000235:genetics*; D002295:Carcinoma, Transitional Cell / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D014644:Genetic Variation; D006720:Homozygote; D006801:Humans; D007438:Introns / Q000235:genetics*; D007668:Kidney; D007680:Kidney Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D018807:Polymorphism, Single-Stranded Conformational; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D001743:Urinary Bladder; D001749:Urinary Bladder Neoplasms / Q000235:genetics*
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human