Genetic basis for kidney cancer: opportunity for disease-specific approaches to therapy

Abstract

Background: Kidney cancer is not a homogenous entity; it is comprised of many different tumor types, with different biologies and molecular mechanisms leading to disease and therefore different treatment approaches.

Objective: To describe the genetic basis and biochemical pathways underlying inherited forms of renal cancer, specifically in four described syndromes (von Hippel-Lindau [VHL], hereditary papillary renal cancer [HPRC], Birt-Hogg-Dubé [BHD] and hereditary leiomyomatosis renal cell carcinoma [HLRCC]), and to elucidate how the understanding of these diseases enables the possibility of disease-specific approaches to therapy.

Methods: A systematic review of the published literature on inherited and sporadic forms of renal cancer was performed.

Conclusion: Understanding of the biology and mechanisms of different forms of kidney cancer provides an opportunity for development of new treatment options.

Figure 1

Kidney cancer is not a single disease; it is made up of a number of different types of cancer that occur in the kidney, each with different histologic types, having a different clinical course, and associated with alteration of a different gene. Percentages represent the frequency of the renal carcinoma subtype. (From LINEHAN WM, WALTHER MM, ZBAR B: The genetic basis of cancer of the kidney. The Journal of urology (2003) 170(6 Pt 1):2163-2172.)[2]

Figure 2

Molecular targeting of the VHL pathway in clear cell renal carcinoma: Mutation of the VHL gene in clear cell kidney cancer results in increased accumulation of HIF and the resulting increase in transcription of downstream targets such as VEGF, Glut-1, and TGFα (A). Mutation of the VHL gene in the α domain (demonstrated here) inhibits binding to elongin C and formation of the VHL complex.[31] Mutations in other parts of the gene, such as the β domain, prevents binding to and ubiquitin mediated degradation of HIF.[32] Potential disease-specific therapeutic approaches include agents which block the function of HIF (B), VEGFR, or EGFR (C). (From LINEHAN WM, ZBAR B: Focus on kidney cancer. Cancer cell (2004) 6(3):223-228.)[35]

Figure 3

Non-renal manifestations of BHD: (A-D) Multiple fibrofolliculomas and (E) multiple pulmonary cysts. (Adapted from LINEHAN WM, WALTHER MM, ZBAR B: The genetic basis of cancer of the kidney. The Journal of urology (2003) 170(6 Pt 1):2163-2172. and TORO JR, GLENN G, DURAY P et al.: Birt-Hogg-Dubé syndrome: a novel marker of kidney neoplasia. Archives of dermatology (1999) 135(10):1195-1202.)[2,55]

Figure 4

Non-renal clinical manifestations of HLRCC: (A,B) cutaneous leiomyomas in a grouped and segmental distribution, (C) multiple large uterine fibroids in a female patient. (Adapted from TORO JR, NICKERSON ML, WEI MH et al.: Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. American journal of human genetics (2003) 73(1):95-106 and LINEHAN WM, WALTHER MM, ZBAR B: The genetic basis of cancer of the kidney. The Journal of urology (2003) 170(6 Pt 1):2163-2172.)[2,69]

Figure 5

Normoxia: In the presence of oxygen (as a substrate), HIF is hydroxylated by HPH, which allows the VHL complex to recognize and target it for ubiquitin-mediated degradation in the proteosome. HLRCC: Loss of FH shunts the TCA cycle to produce excess fumarate. Fumarate stabilizes HIF through competitive inhibition of HPH, allowing HIF to remain unhydroxylated and thus avoiding degredation. Elevated HIF drives transcription products involved with angiogenesis (VEGF), glucose transport (GLUT-1), and growth stimulation (TGF-α, PDGF).