Grant: CIHR - ICR / Cancer Research Society Partnership - Research Grants

Background: Renal cell carcinomas (RCC) are tumours that arise from the renal tubules. Due the nature of the disease it is often discovered late and about 1/4th of the cases have a very poor prognosis. Yearly 7500 Canadians will be diagnosed with kidney cancer, and 1950 Canadians would die of the disease. Hence, it is essential to manage early, localized, renal cancer before it progresses into late or metastatic stages. Early renal cancer disease is identified clinically as pathological stage pT1a < 4cm in size and designated as “small renal masses”, SRM. On the other hand, many SRMs remain indolent for years and don’t progress. The current available treatment modalities of renal cancer can all be associated with co-morbidities such as surgical complications and an increased risk of chronic kidney disease. A more conservative active surveillance approach would be ideal for these indolent masses and particularly for patients that are at risk for treatment complications. Thus, it is important to identify the early lesions that have the potential to progress to aggressive disease, from the more indolent lesions, and selectively treat them with definitive modalities. Patients with end-stage renal disease (ESRD) have an increased risk of developing RCCs that tends to be also bilateral and multifocal. A field effect in ESRD that promote tumour development has been proposed. In our previous work on RCC we investigated a possible progenitor/regenerative cell population in the renal tubular epithelial cells that is increased upon kidney injury and was found to be biologically similar to RCC subtypes. Consequently, ESRD and established renal cancer precursor lesions can be assessed in the time-line progression of renal cancer to establish the mechanism of disease evolution. This proposal attempts to discover biomarkers that can aid in the clinical management decisions of early renal cancer disease, through studying the stepwise tumour’s progression from precancer lesions. Hypothesis: Understanding the stepwise pathogenesis of renal cell carcinoma would allow for the detection of biomarkers that can be tested in early renal cancer disease to predict its progression Aims: 1. To investigate the progression in time of molecular events that lead to the development of renal cell carcinoma as in our proposed model of tumour progression Normal kidney to end stage renal disease kidneys (with enriched precancer cells) to precursor cancer lesions to renal cell carcinoma lesions The different disease stages will be assessed with comprehensive molecular platforms to generate a disease evolution map and to identify key molecular events that cause the transition to each of the subsequent disease stages 2. To identify prognostic biomarkers that can be tested for in small renal masses to predict the potential of renal cell carcinoma progression Significant molecular markers that are identified as part of the disease progression from early lesions will be validated in an in silico renal cancer cohorts using univariate and multivariate survival analysis. The purpose is to identify biomarkers that can predict renal cancer progression Expected outcome and Significance: The aim of this proposal is to understand early events that lead to renal cell carcinoma development and detect biomarkers of early disease progression. The findings would translate to prediction of early tumour behaviour and guide the management strategies of early renal cancer disease for better patient care.