Type II TGF Beta Receptor and RCC Progression

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DESCRIPTION (provided by applicant): Incidence rates for renal cell carcinoma (RCC) have risen steadily over the past three decades with the greatest increases reported for localized tumors. To date, the mainstay of treatment for patients with localized RCC remains surgical excision. Unfortunately, despite aggressive surgical therapy, over 30% of RCC patients with no evidence of metastasis at time of surgery will subsequently develop distant metastases (i.e. disease progression) and roughly two-thirds of those will occur within the first year after surgery. Therefore, an important and controversial issue in renal cancer research is the identification of prognostic factors that correlate with risk of progression following surgery for localized disease. While some investigators have recently published sophisticated scoring algorithms that predict risk of RCC progression, these algorithms are based entirely on clinical and pathologic indices. As such, they represent only surrogate measures for the underlying molecular characteristics that determine tumor aggressiveness and for that reason themselves do not provide potential targets for therapeutic intervention. This limitation underscores a clear need to identify molecular prognostic factors that have the potential to not only improve prediction of RCC progression but also provide potential targets for clinical intervention. Recently, members of our investigative team published compelling genomic array data that implicates loss of expression of the type II transforming growth factor beta receptor (TbetaR2) as a significant event in the acquisition of metastatic phenotype for RCC. Moreover, these array data have been validated (real time PCR, immunohistochemistry, mouse model) and are consistent with other previous studies that also suggest loss of TbetaR2 is an important event in RCC progression. In this investigation, we propose to translate these compelling laboratory data to a clinical population by determining if TbetaR2 expression is associated with RCC progression in a cohort of 369 patients treated surgically for localized RCC at the Mayo Clinic Rochester between January 1, 2000 and December 31, 2003. Explicitly, we will test the hypothesis that lower TbetaR2 expression is associated with an increased risk of RCC progression in both a univariate and multivariate setting. As part of our secondary analyses, we will also examine the role of expression of five downstream targets of TbetaR2 signaling that were also identified as aberrantly regulated in our genomic profiling study. In summary, we will evaluate an innovative translational hypothesis regarding molecular determinants of RCC progression in order to better understand the pathogenesis of this disease and potentially inform on novel treatment regimens.