TGF-␤ 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-␤ 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 G3 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 2 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 TG-FBR1 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. © 2004 Wiley-Liss, Inc. Key words: TGF-␤ type 1 receptor; renal cell carcinoma; bladder transitional cell carcinoma; upper urinary tract transitional cell carcinoma; genetic variant; SSCPCancer of the urinary system is among the 5 most frequent malignancies in the United States based on recent cancer statistics. 1 More than 7% of all cancers in 2004 will be cancers of the kidney or urinary bladder. RCCs, which kill nearly 35% of afflicted patients, account for the majority of kidney neoplasms. TCC of the bladder and upper urinary tract is the fourth most frequent malignancy in men. 1 Advances in the genetic understanding of renal neoplasms have been made through successful cloning and mutational screening of the VHL, TSC and MET proto-oncogenes. However, many sporadic RCCs lack evidence of involvement of these 3 genes. Thus, other genes involved in cell growth regulation may be associated with sporadic RCC. Acquisition of TGF-␤ resistance has been suggested to be an important progression factor in human RCC and bladder TCC. 2,3 Disruption of the TGF-␤ signaling pathway has been hypothesized as the predominant mechanism through which many types of tumor cells gain a selective growth advantage. 4 We focused on the TGFBR1 gene, an important component of the TGF-␤ signaling pathway, for genetic analysis in cancers of the kidney and urinary bladder.The TGF-␤ signal is transduced by 2 transmembrane serinethreonine kinase receptors. TGF-␤ binds first to TGFBR2 homodimers, which then form heterotetramers with 2 TGFBR1 molecules. As a consequence, the TGFBR2 kinase phosphorylates and activates TGFBR1. ...