The Genetic Basis of Kidney Cancer: Implications for Management and Use of Targeted Therapeutic Approaches

Abstract

Each year there are >270 000 cases and 115 000 deaths from kidney cancer worldwide [1]. Although localized kidney cancer is most often treated successfully with surgery, patients who present with advanced disease have 2-yr survival of <20%. Kidney cancer is not a single disease; it is composed of a number of diseases, each of which has a different genetic cause, a clinical course that can be predicted on the basis of genotype, a different histology, and a unique response to therapy. Fifteen genes, including von HippelLindau (VHL), met proto-oncogene (MET), folliculin (FLCN), fumarate hydratase (FH), succinate dehydrogenase (SDH), tuberous sclerosis 1 (TSC1), tuberous sclerosis 2 (TSC2), phosphatase and tensin homolog (PTEN), transcription factor binding to IGHM enhancer 3 (TFE3), transcription factor EB (TFEB), and microphthalmia-associated transcription factor (MITF), have been found to cause or to be associated with the development of either sporadic or inherited forms of kidney cancer [2,3]. In the last 5 yr, there has been considerable progress in the development of therapeutic approaches that target the VHL pathway in clear cell kidney cancer. Seven novel agents—sunitinib, sorafenib, bevacizumab, temsirolimus, everolimus, pazaponib, and, just recently, axitinib—have been approved in the United States for the treatment of patients with advanced kidney cancer. Although these exciting targeted therapeutic agents have benefited many patients, there are currently few documented complete responses to therapy with the use of any of these agents, and most patients eventually develop progressive disease. Understanding the genetic basis of cancer of the kidney has been the critical foundation that has led to improved methods for molecular diagnosis and to the development of targeted approaches to therapy for various kidney cancers. In the early 1990s, the gene for the hereditary form of clear cell kidney cancer associated with VHL was identified [4]. Significant insight about growth rates as well as metastasis rates of VHL gene mutation–associated clear cell kidney cancer has been gained from the longitudinal studies of patients with VHL-associated kidney cancer. In careful follow-up of hundreds of patients with VHLassociated clear cell kidney cancer managed over a 20-yr period, no patient on active surveillance using highly sensitive imaging techniques developed metastases when kidney tumors were removed surgically before the largest tumor grew to a 3-cm-diameter size. In VHL patients, these tumors had a known genetic mutation of the VHL gene. Clear cell kidney cancer makes up approximately 75% of the cases of sporadic, noninherited kidney cancer. The VHL gene has been found to be mutated (or silenced by methylation) in 80–90% of tumors from patients with sporadic, noninherited kidney cancers [5]. The genes that cause non-VHL mutated clear cell kidney cancer are not yet known. Recently, histone modifying genes, including polybromo 1 (PBRM1), were found to be mutated in a significant subset of clear cell kidney cancers [6]. Clear cell kidney cancers have also been found in patients with germline mutations of TSC1, TSC2, FLCN, and FH, but patients with these genotypes more commonly present with different histologic patterns, including papillary cancer. In their article in European Urology, Kroeger et al. report analysis of immunohistochemical staining profiles on 196 randomly selected kidney cancers from 1989 to 2000 and cytogenetic characterization of 272 clear cell kidney cancers from 1989 to 2007 to characterize the determinants of lymphatic spread [7]. Analysis of the immunohistochemical staining revealed a strong correlation between decreased