title: The roles of chromatin-remodelers and epigenetic modifiers in kidney cancer.
abstract: Clear cell renal cell carcinoma (ccRCC) is the major subtype of kidney cancer that is characterized by frequent inactivation of the von Hippel-Lindau (VHL) gene in 80-90% of the tumors. Recent reports using massive parallel sequencing technologies have discovered additional cancer driver genes. PBRM1 was found to be mutated in about 40% of ccRCC tumors, whereas BAP1 and SETD2 were each mutated in about 10-15% of ccRCC tumors. JARID1C and UTX, two histone H3 demethylases, were also found to harbor mutations in ccRCC, albeit at lower rates. ccRCC tumors display a high degree of intra-tumoral heterogeneity, with some mutations present in all cancer cells (ubiquitous), whereas others are subclonal. The VHL mutations were always ubiquitous in the tumors; PBRM1 mutations were also ubiquitous but to a lesser extent. On the contrary, mutations in BAP1, SETD2, JARID1C, and UTX were all subclonal, meaning that they were present in a subset of cancer cells in a tumor. The prognostic value of PBRM1 mutations in ccRCC is still controversial, whereas BAP1 mutations were tightly linked to worse clinical outcomes in multiple studies. The molecular functions of these newly identified cancer driver genes are discussed, and they were known readers, writers, or erasers of histone marks on histone H2 and H3 tails that are very close to each other, suggesting that these factors might functionally interact and affect common pathways. The studies on these newly identified tumor suppressors will shed light on ccRCC tumorigenesis and development, and will likely lead to development of novel therapeutic interventions for ccRCC patients.
authors: Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA.
authors: Lili
authors: L
authors: Liao
authors: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA.
authors: Joseph R
authors: JR
authors: Testa
authors: Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA. Electronic address: haifeng.yang@jefferson.edu.
authors: Haifeng
authors: H
authors: Yang
mesh_terms: D000818:Animals; D002292:Carcinoma, Renal Cell / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002843:Chromatin / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly / Q000235:genetics*; D004268:DNA-Binding Proteins; D015972:Gene Expression Regulation, Neoplastic; D056466:Histone Demethylases / Q000235:genetics; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics*; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics; D043222:Ubiquitin Thiolesterase / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics
chemical_list: C400134:BAP1 protein, human; D002843:Chromatin; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C102195:PBRM1 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D056466:Histone Demethylases; C523998:KDM6A protein, human; D011495:Histone-Lysine N-Methyltransferase; C521636:SETD2 protein, human; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D043222:Ubiquitin Thiolesterase; C497446:VHL protein, human
keywords: BAP1; JARID1C/KDM5A; PBRM1; SETD2; VHL