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J Clin Oncol. 2014 Jun 20;32(18):1968-76. doi: 10.1200/JCO.2012.45.2003. Epub 2014 May 12.

Molecular genetics of clear-cell renal cell carcinoma.

Author information

1
From the Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX. james.brugarolas@utsouthwestern.edu.

Abstract

Renal cell carcinoma of clear-cell type (ccRCC) is an enigmatic tumor type, characterized by frequent inactivation of the VHL gene (infrequently mutated in other tumor types), responsiveness to angiogenesis inhibitors, and resistance to both chemotherapy and conventional radiation therapy. ccRCC tumors exhibit substantial mutation heterogeneity. Recent studies using massively parallel sequencing technologies have implicated several novel driver genes. In VHL wild-type tumors, mutations were discovered in TCEB1, which encodes Elongin C, a protein that binds to VHL and is required for its function. Several additional tumor suppressor genes have been identified near the VHL gene, within a region that is frequently deleted in ccRCC on chromosome 3p: SETD2, BAP1, and PBRM1. Mutations in BAP1 and PBRM1 are largely mutually exclusive and are associated with different tumor biology and patient outcomes. In addition, the mTORC1 pathway is deregulated by mutations in MTOR, TSC1, PIK3CA, and PTEN in approximately 20% of ccRCCs. Mutations in TSC1, and possibly other genes, may predict for sensitivity to mTORC1 inhibitors. These discoveries provide insight into ccRCC development and set the foundation for the first molecular genetic classification of the disease, paving the way for subtype-specific therapies.

PMID:
24821879
PMCID:
PMC4050206
DOI:
10.1200/JCO.2012.45.2003
[Indexed for MEDLINE]
Free PMC Article

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