© 2007 THE AUTHORS 1208 JOURNAL COMPILATION © 2 0 0 7 B J U I N T E R N A T I O N A L | 9 9 , 1 2 0 8 – 1 2 11 | doi:10.1111/j.1464-410X.2007.06812.x Rev Article MOLECULAR MARKERS IN RENAL CELL CARCINOMA LEPPERT et al. The role of molecular markers in the staging of renal cell carcinoma John T. Leppert, Allan J. Pantuck, Robert A. Figlin and Arie S. Belldegrun Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA classifications of RCC. Molecular markers will also advance current staging systems and improve prognostic information for patients and clinicians. Finally, the molecular signature of RCC tumours will allow for sophisticated application of systemic and targeted therapies, improving patient response and minimizing unnecessary exposure of patients to treatment toxicities. We review the significance of molecular markers in the understanding of tumour biology, and the development of future staging paradigms and treatment strategies for RCC. THE DEVELOPMENT OF STAGING SYSTEMS: FROM MACRO TO MICRO TO MOLECULAR Staging systems for kidney cancer serve to provide: (i) a description of the size and spread of a tumour; (ii) aid in selecting therapeutic options for each patient; (iii) accurate prognostic information to stratify risk of disease recurrence or cancer-related death; (iv) criteria to identify patient populations for specific adjuvant therapies; and (v) inclusion criteria for clinical trials [4]. RCC staging systems have developed in parallel with the rapid increase in understanding of renal tumour biology. The first formal staging systems, proposed by Flocks and Kadesky [5] and later modified by Robson et al. [6], used the anatomical information available to clinicians at the time. Numerous refinements have led to the current TNM system proposed by the Union Internationale Contre le Cancer [7]. Integrated staging systems have been revised to include a myriad of pathological, histological and clinical characteristics that have been shown to be prognostic indicators for RCC. For example, the UCLA Integrated Staging System (UISS) supplements the anatomical TNM staging with the Eastern Cooperative Oncology Group performance status and the Fuhrman grade of the tumour [8]. The UISS, as well as other integrated staging systems such as the Kattan postoperative nomogram [9], have been shown to be powerful tools with improved prognostic ability compared to anatomical staging alone [10,11]. As research advances our understanding of the molecular and genetic biology of kidney cancer, including important genetic and protein molecular markers represents the next logical advance in RCC staging systems. MOLECULAR STAGING SYSTEMS The expression of gene/protein markers might provide prognostic information as: (i) surrogate markers of tumour aggressiveness; (ii) a mechanism directly involved in tumour growth or metastasis; (iii) antigens recognized by the host immune system; (iv) markers that serve as the targets of targeted therapies, or that predict response to treatments. CARBONIC ANHYDRASE IX (CAIX) AS AN EXAMPLE OF A PROGNOSTIC MOLECULAR MARKER Significant attention has been paid to CAIX (also known as G250 or MN), a member of the CA family. CAIX is thought to assist in regulating intracellular and extracellular pH levels in response to tumoral hypoxia and subsequent anaerobic metabolism. In one study, CAIX was detected in 86% of RCC samples studied, but was found in only 9% of normal kidney tissue samples, suggesting that CAIX expression might be a useful diagnostic biomarker [12]. A study at UCLA found that 94% of clear cell RCC tumour samples stained positively for CAIX, while expression was completely absent in benign tumours such as oncocytoma [13]. Low levels of CAIX staining were an independent indicator of poor survival in patients with metastatic RCC (hazard ratio 3.10). For patients with localized, high-risk RCC lesions, low CAIX staining also implied a worse prognosis. CAIX represents the potential of a single molecular marker to stratify patient prognosis. Finally, CAIX also represents a potential therapeutic target. KEYWORDS molecular markers, kidney cancer, staging, prognosis INTRODUCTION Cancers of the kidney are estimated to account for 38 890 new cases and 12 840 deaths in the USA in 2006 [1]. RCC is a highly aggressive tumour; a third of patients will have evidence of metastasis at the time of diagnosis [2] and > 40% of patients with RCC will die from their disease [3]. Advances in imaging, staging and the treatment have led to a significant and progressive increase in relative 5-year survival rates for patients with RCC [1]. Despite these advances, the heterogeneous nature of the disease remains a clinical challenge. RCC comprises a family of epithelial tumours arising from within the kidney. Each subtype of RCC presents a unique clinical picture, with varied tumour biology, patient prognosis and response to treatment. Furthermore, there is a wide disparity in clinical outcomes for patients even within specific RCC subtypes. These challenges underscore the critical importance of accurate indicators of prognosis for this patient population. Historically, staging paradigms have been refined to move ever closer to a fixed goal; accurate prognostic information for individual patients and clinicians. Recent breakthroughs have led to greater knowledge of the molecular genetics and oncogenic pathways of kidney cancer. These advances have led directly to novel and exciting therapies for RCC. The overall prognosis for patients with localized and advanced RCC is likely to improve in step with these emerging therapies, necessitating a rapid reassessment of RCC staging constructs. Protein and gene expression analysis promise to aid in recapitulating and, in the near future, to further refine the current histological