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Kidney Cancer Genomics: Paving the Road to a New Paradigm of Personalized Medicine

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Cancer Genomics

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Abstract

Renal cell carcinoma (RCC) is the most common neoplasm of the adult kidney. Unlike other cancers, its incidence has risen in the past 20 years. The most common subtype of RCC is clear cell RCC (ccRCC) which accounts for approximately 70–80% of cases. A number of genetic aberrations have been reported to be associated with RCC. These include mutations of the von-Hippel Lindau tumor suppressor (VHL) gene which can be associated with a hereditary form of RCC. Inactivation of VHL leads to the stabilization of hypoxia-inducible factors (HIFs) which activates a number of downstream target proteins and contributes to cell proliferation and migration. Currently, there are no established tumor markers for RCC in clinical practice. Recently, a number of molecular markers have been examined as potential diagnostic and prognostic markers for RCC but none have gained clinical application. The new era of molecular profiling has broadened the potential discovery of biomarkers for RCC. This approach allows simultaneous comparison of thousands of molecules in one experiment which will lead to a better understanding of the pathways that are involved in RCC pathogenesis. Molecular profiling can benefit RCC patients at multiple levels including the improvement of early diagnosis, accurate tumor subclassification, prognosis, and prediction of treatment response. In this chapter, we provide a comprehensive review of the genomics of renal cell carcinoma and describe known genetic alterations that are associated with each RCC subtype. We present the current status of tumor markers in RCC and discuss the use of molecular profiling in RCC through different approaches. We also describe the clinical applications of molecular profiling in RCC and how this approach may improve personalized medicine for RCC patients. Finally, we discuss the concept of“integrated genomics” and how this can be applied to further the understanding of the pathogenesis of RCC.

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Abbreviations

AMPK:

AMP-activated protein kinase

BHD:

Birt-Hogg-Dubé

CAIX:

Carbonic anhydrase IX

CAV1:

Caveolin-1

ccRCC:

Clear cell renal cell carcinoma

CGP:

Cancer Genome Project

chRCC:

Chromophobe renal cell carcinoma

CNA:

Copy-number alteration

EPAS1:

Endothelial PAS domain protein 1

FH:

Fumarate hydratase

FLCN:

Folliculin

GWAS:

Genome-wide association study

HIF:

Hypoxia-inducible factors

HIF2α:

Hypoxia-inducible factor-2 alpha

HLRCC:

Hereditary leiomyomatosis renal cell carcinoma

HRPCC:

Hereditary papillary renal cell carcinoma

LOH:

Loss of heterozygosity

MHC:

Major histocompatibility complex

mTOR:

Mammalian target of rapamycin

NF2:

Neurofibromin 2

PDGF:

Platelet-derived growth factor

Phos-S6:

Phosphorylated ribosomal protein S6 kinase

pRCC:

Papillary renal cell carcinoma

pVHL:

VHL protein

RCC:

Renal cell carcinoma

TFE3:

Transcription factor E3

TGFα:

Transforming growth factor-alpha

TGFβ:

Transforming growth factor-beta

UMPP:

Ubiquitin-mediated proteolysis pathway

VEGF:

Vascular endothelial growth factor

VHL:

Von-Hippel Lindau tumor suppressor

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  1. Department of Laboratory Medicine, Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Canada, M5B 1W8

    George M. Yousef, Nicole M. A. White & Andrew H. Girgis

  2. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada, M5S 1A8

    George M. Yousef & Nicole M. A. White

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    Ulrich Pfeffer

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Yousef, G.M., White, N.M.A., Girgis, A.H. (2013). Kidney Cancer Genomics: Paving the Road to a New Paradigm of Personalized Medicine. In: Pfeffer, U. (eds) Cancer Genomics. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-5842-1_7

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