Using tumor markers to predict the survival of patients with metastatic renal cell carcinoma
ABSTRACT Approximately 30% of renal cell carcinomas (RCCs) present as metastatic disease. Molecular markers have the potential to characterize accurately the biological behavior of tumors and they may be useful for determining prognosis.
A custom tissue array was constructed using clear cell RCC from 150 patients with metastatic RCC who underwent nephrectomy prior to immunotherapy. The tissue array was stained for 8 molecular markers, namely Ki67, p53, gelsolin, carbonic anhydrase (CA)9, CA12, PTEN (phosphatase and tensin homologue deleted on chromosome 10), epithelial cell adhesion molecule and vimentin. Marker status and established clinical predictors of prognosis were considered when developing a prognostic model for disease specific survival.
On univariate Cox regression analysis certain markers were statistically significant predictors of survival, namely CA9 (p <0.00001), p53 (p = 0.0072), gelsolin (p = 0.030), Ki67 (p = 0.036) and CA12 (p = 0.043). On multivariate Cox regression analysis that included all markers and clinical variables CA9 (p = 0.00002), PTEN (p <0.0001), vimentin (p = 0.0032), p53 (p = 0.028), T category (p = 0.0025) and performance status (p = 0.0013) were significant independent predictors of disease specific survival and they were used to construct a combined molecular and clinical prognostic model. The bias corrected concordance index (C-index) of this combined prognostic model was C = 0.68, which was significantly higher (p = 0.0033) than that of a multivariate clinical predictor model (C = 0.62) based on the UCLA Integrated Staging System (T category, histological grade and performance status).
In patients with clear cell RCC a prognostic model for survival that includes molecular and clinical predictors is significantly more accurate than a standard clinical model using the combination of stage, histological grade and performance status.
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- "The ultimate goal of developing biomarkers is the clinical application. The best example of synthesising pathological , clinical and molecular markers into one prognostic schema was from Kim et al. , who developed a nomogram predicting disease-specific mortality rates in metastatic RCC which takes into account Tstage , performance status, CA-9, vimentin, p53 and PTEN. This model outperformed the validated University of California Los Angeles Integrated Staging System  , which only takes into account TNM stage, Fuhrman grade and performance status. "
ABSTRACT: Objectives Increased knowledge about the molecular pathways involved in tumorigenesis has led to the discovery of new prognostic molecular markers and development of novel targeted therapies for renal cell carcinoma (RCC). In this review we describe the prognostic markers of RCC and highlight the areas of recent discovery with a focus on the mammalian target of rapamycin (mTOR) pathway.Methods We reviewed previous reports, using PubMed with the search terms ‘renal cell carcinoma’, ‘molecular markers’, ‘prognosis’, ‘outcomes’ and ‘mammalian target of rapamycin pathway’ published in the last two decades. We created a library of 100 references and focused on presenting the recent advances in the field.ResultsGrowing evidence suggests that mTOR deregulation is associated with many types of human cancer, including RCC. Consequently, temsirolimus and everolimus, which target mTOR, are approved for treating advanced RCC. There is a demand to integrate clinical, pathological and molecular markers into accurate prognostic models to provide patients with the most personalised cancer care possible.Conclusions The mTOR pathway is highly implicated in RCC tumorigenesis and progression, and its constituents might represent a promising prognostic tool and target for treating RCC. Combining newly discovered molecular markers with classic clinicopathological prognostics might potentially improve the management of RCC.06/2012; 10(2):110–117. DOI:10.1016/j.aju.2012.02.005
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- "APAF1/DAPK1 Christoph et al. (2006b) RASSF1A/PTGS2/CDH1 Costa et al. (2007) PTEN Kim et al. (2005) Histone modifications & modifiers NA H3K4me2/H3K18Ac Seligson et al. (2009) H3K4me1/H3K4me2/H3K4me3 Ellinger et al. (2010) H3K18Ac Mosashvilli et al. (2010) miRNA miR-141/miR-155 Jung et al. (2009) miR-32 Petillo et al. (2009) miR-1233 Wulfken et al. (2011) NA, not available. miR-191, miR-199a-3p, miR-19a, miR-215, miR-29b, miR-30c, miR-363, miR-9) and others of hereditary (Von Hippel–Lindau syndrome-related) RCC (let-7a, miR-125a-5p, miR-125b, miR- 143, miR-146b-5p, miR-15b, miR-17, miR-193a-5p, miR-193b, miR-196a, miR-20b, miR-214, miR-23b, miR-32, miR-372; Valera et al., 2011). "
ABSTRACT: Renal cell tumors (RCT) collectively constitute the third most common type of genitourinary neoplasms, only surpassed by prostate and bladder cancer. They comprise a heterogeneous group of neoplasms with distinctive clinical, morphological, and genetic features. Epigenetic alterations are a hallmark of cancer cells and their role in renal tumorigenesis is starting to emerge. Aberrant DNA methylation, altered chromatin remodeling/histone onco-modifications and deregulated microRNA expression not only contribute to the emergence and progression of RCTs, but owing to their ubiquity, they also constitute a promising class of biomarkers tailored for disease detection, diagnosis, assessment of prognosis, and prediction of response to therapy. Moreover, due to their dynamic and reversible properties, those alterations represent a target for epigenetic-directed therapies. In this review, the current knowledge about epigenetic mechanisms and their altered status in RCT is summarized and their envisaged use in a clinical setting is also provided.Frontiers in Genetics 05/2012; 3(3):94. DOI:10.3389/fgene.2012.00094
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- "In renal cell cancer, PTEN gene expression has been shown to be downregulated in a large percentage of cases, presumably by epigenetic silencing (Brenner et al, 2002; Velickovic et al, 2002). In particular, lack of PTEN expression has been shown to be an independent negative prognostic factor for diseasespecific survival in patients with metastatic renal cell carcinoma (Kim et al, 2005). However, in culture, most of the renal cancer cell lines remain poorly sensitive to rapalogues. "
ABSTRACT: The proof of principle that a drug targeting mTOR can improve survival has been obtained recently from a large randomised trial using temsirolimus as a first-line therapy in patients with advanced poor prognostic renal cell carcinoma. Consistent data have recently shown the important role of the PI3K/AKT/mTOR signalling pathway in the regulation of crucial metabolic and mitotic functions of cancer cells and endothelial cells allowing a better understanding of the role of mTOR in controlling cancer cell proliferation and survival as well as tumour angiogenesis. As a result, rapamycin derivatives (rapalogues) that block mTOR/Raptor complex 1 were shown to exert direct antiproliferative effects against endometrial cancers, in which cancer cells frequently lose PTEN function as well as mantle cell lymphomas, in which cancer cell proliferation appears to be driven primarily by cyclin D1 overexpression. The overall antitumour effects of rapalogues in renal cell carcinoma appear to be more complex with tumour growth inhibition resulting from direct G1/S cell cycle blockage and/or apoptotic effects in carcinoma cells along with the inhibition of downstream signalling of the HIF1alpha-induced VEGF/VEGFR autocrine loop in endothelial cells shutting down the maintenance of tumour angiogenesis. Despite extensive cognitive researches, it is difficult to appraise which of those mechanisms is predominant in patients. This review focuses on mechanisms of action of rapalogues focusing on antitumour effects in patients with renal cell carcinoma.British Journal of Cancer 10/2008; 99(8):1197-203. DOI:10.1038/sj.bjc.6604636 · 4.82 Impact Factor