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Sporadic RCC: Abnormalities in Histone-Modifying Genes

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Renal Cell Carcinoma

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Abstract

Renal cell carcinoma (RCC) is one of the top ten leading causes of cancer death, affecting more than 50,000 patients annually. The median survival of patients with metastatic disease is approximately 2 years with systemic therapy, and the most common histology is clear cell renal cell carcinoma (ccRCC). The molecular mechanism is linked to the inactivation of the von Hippel-Lindau tumor suppressor gene (VHL), which encodes for an oxygen sensor that regulates degradation of the HIF (hypoxia-inducible factor) transcription factor (Latif et al., Science 260(5112):1317–1320, 1993). HIF transactivates target genes involved in cellular adaptation to hypoxia. The mammalian target of rapamycin (mTOR) signaling cascade is often stimulated in ccRCC, and activation of the mTOR kinase pathway further augments HIF levels to subsequently activate HIF-dependent transcription (Barthelemy et al., Crit Rev Oncol Hematol 88(1):42–56, 2013). The elucidation of VHL function and mTOR pathway activation led to the discovery of VEGF and mTOR inhibitors for RCC treatment. Recently, secondary mutations identified in histone-modifying enzymes suggest that chromatin remodeling and alterations of histone modifications may play a role in RCC pathogenesis and prognosis with distinct epigenetic phenotypes. This chapter will focus on summarizing the more prevalent genetic mutations and possible aberrant signaling pathways that contribute to metastatic ccRCC.

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Authors and Affiliations

  1. Center for Translation Cancer Research, Institute for Biosciences & Technology, Texas A&M Health Science Center, Houston, TX, USA

    Ruhee Dere Ph.D.

  2. Division of Hematology and Oncology, Mayo Clinic Arizona, 13400 East Shea Boulevard, Scottdale, AZ, 85295, USA

    Thai H. Ho M.D., Ph.D.

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  1. Ruhee Dere Ph.D.
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Correspondence to Thai H. Ho M.D., Ph.D. .

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  1. Taussig Cancer Center, Cleveland Clinic, Pepper Pike, Ohio, USA

    Ronald M. Bukowski

  2. Division of Hematology Oncology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA

    Robert A. Figlin

  3. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA

    Robert J. Motzer

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Dere, R., Ho, T.H. (2015). Sporadic RCC: Abnormalities in Histone-Modifying Genes. In: Bukowski, R., Figlin, R., Motzer, R. (eds) Renal Cell Carcinoma. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1622-1_6

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