The transforming growth factor-beta (TGF-β) pathway plays an important role in tumor development and progression. There is extensive evidence that TGF-β has antiproliferative effects and can hinder the early steps of tumor progression in several cell types. By contrast, recent evidence has suggested that TGF-β can also play an important role in later steps of tumor progression where it accelerates invasion and metastasis.1, 2
The TGF-β pathway is altered in a wide variety of cancers, including urinary bladder tumors. TGF-β receptors (TGFBR) and other proteins involved in TGF-β signalling, such as Smads, have been shown to be targets of somatic mutations in several cancers including those of the colorectum, pancreas and lung. Furthermore, altered levels of ligand and receptors have been described in the neoplastic tissue.3
More recently, there has been interest in the contribution of genetic variation in this pathway to cancer susceptibility. Several polymorphic variants in genes involved in this pathway have been studied. Single nucleotide polymorphisms (SNPs) in TGFB1 (exon 1: 327 C>T, rs1982073; exon 5: 73 C>T, rs1800472), coding for 1 of the secreted ligands, have been reported to be associated with breast, colorectal, lung and nasopharyngeal carcinomas and non-Hodgkin lymphomas.4–7 A larger number of studies have dealt with genetic variation in TGFBR1, which codes for 1 of the 2 subunits of the heterodimeric membrane receptor kinase.8 The most extensively studied variant allele is TGFBR1*6A, rs11466445, which corresponds to a trinucleotide repeat coding for an Ala repeat. The most common allele among Caucasians contains 9 Ala residues whereas the 6 Ala variant is less common and has been reported to be a susceptibility allele for colorectal and breast cancer.9, 10 Somatic acquisition of this trinucleotide variant has also been reported in colon cancer.11 Very few studies have analyzed its association with bladder cancer risk and their results are not conclusive.12
In this study, we analyzed in a prospectively recruited large case-control population whether 7 different common polymorphisms in genes coding for 2 key members of the TGF-β signalling pathway (TGFB1 and TGFBR1) are associated with bladder cancer risk as well as with patient's prognosis.