The genetic basis of kidney cancer: implications for management and use of targeted therapeutic approaches.

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