Genetic basis of kidney cancer: role of genomics for the development of disease-based therapeutics

Abstract

Kidney cancer is not a single disease; it is made up of a number of different types of cancer, including clear cell, type 1 papillary, type 2 papillary, chromophobe, TFE3, TFEB, and oncocytoma. Sporadic, nonfamilial kidney cancer includes clear cell kidney cancer (75%), type 1 papillary kidney cancer (10%), papillary type 2 kidney cancer (including collecting duct and medullary RCC) (5%), the microphalmia-associated transcription (MiT) family translocation kidney cancers (TFE3, TFEB, and MITF), chromophobe kidney cancer (5%), and oncocytoma (5%). Each has a distinct histology, a different clinical course, responds differently to therapy, and is caused by mutation in a different gene. Genomic studies identifying the genes for kidney cancer, including the VHL, MET, FLCN, fumarate hydratase, succinate dehydrogenase, TSC1, TSC2, and TFE3 genes, have significantly altered the ways in which patients with kidney cancer are managed. While seven FDA-approved agents that target the VHL pathway have been approved for the treatment of patients with advanced kidney cancer, further genomic studies, such as whole genome sequencing, gene expression patterns, and gene copy number, will be required to gain a complete understanding of the genetic basis of kidney cancer and of the kidney cancer gene pathways and, most importantly, to provide the foundation for the development of effective forms of therapy for patients with this disease.

Figure 1.

Kidney cancer is not a single disease; it is made up of a number of cancers that occur in the kidney, each with a distinct histology, each with a different clinical course, each responding differently to therapy, and each caused by a different gene. The VHL gene is mutated in the germline of ∼100% of von Hippel-Lindau families and the majority of sporadic clear cell RCCs. The MET gene is mutated in the germline of ∼100% of hereditary papillary renal carcinoma families and is mutated in a subset of tumors (13%) from patients with sporadic, type 1 papillary kidney cancer. The fumarate hydratase gene (FH) is the gene for the inherited form of type 2 papillary kidney cancer associated with hereditary leiomyomatosis renal cell carcinoma (HLRCC). Sporadic papillary type 2 RCC is composed of a mixture of kidney cancers including collecting duct and medullary RCC. The gene(s) for sporadic type 2 papillary RCC, collecting duct RCC, and medullary RCC is not known. The FLCN is mutated in 96% of families affected with the inherited form of chromophobe RCC and oncocytoma associated with Birt-Hogg-Dubé syndrome. The genes for the sporadic forms of chromophobe RCC and oncocytoma are not known. TFE3, TFEB, and MITF are part of the MiT family of transcription factors. TFE3 and TFEB translocation kidney cancer are sporadic (nonhereditary); germline mutations of MITF have been found in the germline of patients with melanoma and kidney cancer or both. (Fig. 1 adapted from Linehan et al. 2003.)

Figure 2.

Clear cell kidney cancer. Von Hippel-Lindau (VHL) is an autosomal hereditary cancer disorder in which affected individuals are at risk for the development of bilateral, multifocal kidney cancer (A,B) of clear cell histologic type (C). VHL is characterized by germline mutation of the VHL gene (D). The VHL gene is mutated in 57%–89% of sporadic, noninherited clear cell kidney cancers (Gnarra et al. 1994; Moore et al. 2011). (Fig. 2 from Linehan et al. 2003.)

Figure 3.

Type 1 papillary kidney cancer. Hereditary papillary renal carcinoma (HPRC) is an autosomal dominant hereditary cancer syndrome (D) in which affected individuals are at risk for the development of bilateral kidney cancer (A,B) that is type 1 papillary histologic type (C). Patients affected with HPRC are characterized by germline mutation of the MET gene. MET mutations are also found in a subset of tumors (13%) from patients with sporadic, nonhereditary papillary kidney cancer. (Fig. 3 from Linehan et al. 2003.)

Figure 4.

Chromophobe kidney cancer. Birt-Hogg-Dubé (BHD) is an autosomal dominant hereditary cancer syndrome in which affected individuals are at risk for the development of cutaneous fibrofolliculomas, pulmonary cysts, and bilateral, multifocal chromophobe and hybrid oncocytic kidney cancer and oncocytoma. BHD is characterized by germline mutation of the FLCN gene. (Fig. 4 from Linehan et al. 2003.)

Figure 5.

Type 2 papillary kidney cancer. Hereditary leiomyomatosis renal cell carcinoma (HLRCC) is an autosomal dominant hereditary cancer syndrome (right lower panel) in which affected individuals are at risk for the development of type 2 kidney cancer (upper left and upper middle panels), cutaneous leiomyomas (right upper, left lower, and middle lower panels) and early onset uterine leiomyomas (fibroids). HLRCC is characterized by germline mutation of the gene for the Krebs cycle enzyme, fumarate hydratase. (Fig. 5 from Linehan et al. 2003.)

Figure 6.

Kidney cancer gene pathways. Kidney cancer is fundamentally a metabolic disease. Each of the kidney cancer genes, VHL, MET, FLCN, FH, SDH, TSC1, TSC2, and TFE3 affects the cell's ability to sense oxygen, iron, nutrients, and most particularly in the Krebs cycle enzymes, FH and SDH, and energy. Further genomics studies elucidating these kidney cancer gene pathways will provide the foundation for the development of targeted approaches for therapy for these diseases. (Fig. 6 adapted from Linehan et al. 2010.)