Abstract
Prostate cancer (PC) is the most frequently diagnosed cancer in men. The acquisition of castration-resistant (CR) phenotype is associated with the activation of signaling pathways mediated by growth factors. The TGFβ1 and its receptors have an important role in tumor progression, being the pro-apoptotic function modulated by the expression of TGFBR2. A single nucleotide polymorphism -875 G > A in TGFBR2 gene has been described, which may influence the expression levels of the receptor. Our purpose was to investigate the potential role of TGFBR2-875G>A in PC risk and in the response to androgen deprivation therapy (ADT). TGFBR2-875G>A polymorphism was studied by allelic discrimination using real-time polymerase chain reaction (PCR) in 891 patients with PC and 874 controls. A follow-up study was undertaken to evaluate response to ADT. The TGFBR2 and SMAD7 mRNA expression were analyzed by a quantitative real-time PCR. We found that TGFBR2-875GG homozygous patients present lower expression levels of TGFBR2 mRNA (AA/AG: 2(-ΔΔCT) =1.5, P=0.016). GG genotype was also associated with higher Gleason grade (OR=1.51, P=0.019) and increased risk of an early relapse after ADT (HR=1.47, P=0.024). The concordance (c) index analysis showed that the definition of profiles that contains information regarding tumor characteristics associated with genetic information present an increased capacity to predict the risk for CR development (c-index model 1: 0.683 vs model 2: 0.736 vs model 3: 0.746 vs model 4: 0.759). The TGFBR2-875G>A contribution to an early relapse in ADT patients, due to changes in mRNA expression, supports the involvement of TGFβ1 pathway in CRPC. Furthermore, according to our results, we hypothesize the potential benefits of the association of genetic information in predictive models of CR development.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Aged
-
Alleles
-
Androgen Antagonists / therapeutic use
-
Androgens / metabolism
-
Case-Control Studies
-
Gene Expression Regulation, Neoplastic*
-
Genotype
-
Homozygote
-
Humans
-
Kallikreins / genetics
-
Kallikreins / metabolism
-
Likelihood Functions
-
Male
-
Middle Aged
-
Neoplasm Recurrence, Local / diagnosis
-
Neoplasm Recurrence, Local / drug therapy
-
Neoplasm Recurrence, Local / genetics*
-
Neoplasm Recurrence, Local / mortality
-
Polymorphism, Single Nucleotide*
-
Prognosis
-
Prostate / drug effects
-
Prostate / metabolism
-
Prostate / pathology
-
Prostate-Specific Antigen / genetics
-
Prostate-Specific Antigen / metabolism
-
Prostatic Neoplasms / diagnosis
-
Prostatic Neoplasms / drug therapy
-
Prostatic Neoplasms / genetics*
-
Prostatic Neoplasms / mortality
-
Protein Serine-Threonine Kinases / genetics
-
Protein Serine-Threonine Kinases / metabolism*
-
Receptor, Transforming Growth Factor-beta Type II
-
Receptors, Transforming Growth Factor beta / genetics
-
Receptors, Transforming Growth Factor beta / metabolism*
-
Signal Transduction
-
Survival Analysis
-
Transforming Growth Factor beta1 / genetics
-
Transforming Growth Factor beta1 / metabolism*
Substances
-
Androgen Antagonists
-
Androgens
-
Receptors, Transforming Growth Factor beta
-
Transforming Growth Factor beta1
-
Protein Serine-Threonine Kinases
-
Receptor, Transforming Growth Factor-beta Type II
-
KLK3 protein, human
-
Kallikreins
-
Prostate-Specific Antigen
Grants and funding
The authors would like to thank the Liga Portuguesa Contra o Cancro—Centro Regional do Norte (Portuguese League Against Cancer) and Fundação para a Ciência e Tecnologia (FCT), this project was partially sponsored by an unrestricted educational grant for basic research in molecular oncology from FCT (PTDC/SAU-FCF/71552/ 2006). ALT is a Doctoral degree grant holder from FCT (SFRH/BD/47381/2008). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.