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      BAP1 loss defines a new class of renal cell carcinoma

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          Abstract

          The molecular pathogenesis of renal cell carcinoma (RCC) is poorly understood. Whole-genome and exome sequencing followed by innovative tumorgraft analyses (to accurately determine mutant allele ratios) identified several putative two-hit tumor suppressor genes including BAP1. BAP1, a nuclear deubiquitinase, is inactivated in 15% of clear-cell RCCs. BAP1 cofractionates with and binds to HCF-1 in tumorgrafts. Mutations disrupting the HCF-1 binding motif impair BAP1-mediated suppression of cell proliferation, but not H2AK119ub1 deubiquitination. BAP1 loss sensitizes RCC cells in vitro to genotoxic stress. Interestingly, BAP1 and PBRM1 mutations anticorrelate in tumors ( P=3×10 −5), and combined loss of BAP1 and PBRM1 in a few RCCs was associated with rhabdoid features ( q=0.0007). BAP1 and PBRM1 regulate seemingly different gene expression programs, and BAP1 loss was associated with high tumor grade ( q=0.0005). Our results establish the foundation for an integrated pathological and molecular genetic classification of RCC, paving the way for subtype-specific treatments exploiting genetic vulnerabilities.

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          Most cited references 39

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          Prognostic significance of morphologic parameters in renal cell carcinoma.

          The prognostic significance of morphologic parameters was evaluated in 103 patients with renal cell carcinoma diagnosed during 1961--1974. Pathologic material was classified as to pathologic stage, tumor size, cell arrangement, cell type and nuclear grade. Four nuclear grades (1--4) were defined in order of increasing nuclear size, irregularity and nucleolar prominence. Nuclear grade was more effective than each of the other parameters in predicting development of distant metastasis following nephrectomy. Among 45 patients who presented in Stage I, tumors classified as nuclear grade 1 did not metastasize for at least 5 years, whereas 50% of the higher grade tumors did so. Moreover, among Stage I tumors there was a significant difference in subsequent metastatic rate between nuclear grades 1 and 2. There was an apparent positive relationship between cell type and metastatic rate; clear cell tumors were less aggressive than predominantly granular cell tumors (metastatic rate 38% versus 71%). This relationship in part a function of the nuclear grade: only 5% of grade 3 and 4 tumors consisted of clear cells, whereas such high grades were seen in 57% of granular cell tumors. The size of the primary correlated well with the stage at the time of surgery. However, with the exception of extremely large and small tumors, the size was not useful in predicting the subsequent course of patients treated for Stage I tumors. Nuclear grade was the most significant prognostic criterion for the outcome of Stage I renal cell carcinoma.
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            Mutations of the VHL tumour suppressor gene in renal carcinoma.

            Multiple, bilateral renal carcinomas are a frequent occurrence in von Hippel-Lindau (VHL) disease. To elucidate the aetiological role of the VHL gene in human kidney tumorigenesis, localized and advanced tumours from 110 patients with sporadic renal carcinoma were analysed for VHL mutations and loss of heterozygosity (LOH). VHL mutations were identified in 57% of clear cell renal carcinomas analysed and LOH was observed in 98% of those samples. Moreover, VHL was mutated and lost in a renal tumour from a patient with familial renal carcinoma carrying the constitutional translocation, t(3;8)(p14;q24). The identification of VHL mutations in a majority of localized and advanced sporadic renal carcinomas and in a second form of hereditary renal carcinoma indicates that the VHL gene plays a critical part in the origin of this malignancy.
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              Single-cell exome sequencing reveals single-nucleotide mutation characteristics of a kidney tumor.

               Xun Xu,  Yong Hou,  Xuyang Yin (2012)
              Clear cell renal cell carcinoma (ccRCC) is the most common kidney cancer and has very few mutations that are shared between different patients. To better understand the intratumoral genetics underlying mutations of ccRCC, we carried out single-cell exome sequencing on a ccRCC tumor and its adjacent kidney tissue. Our data indicate that this tumor was unlikely to have resulted from mutations in VHL and PBRM1. Quantitative population genetic analysis indicates that the tumor did not contain any significant clonal subpopulations and also showed that mutations that had different allele frequencies within the population also had different mutation spectrums. Analyses of these data allowed us to delineate a detailed intratumoral genetic landscape at a single-cell level. Our pilot study demonstrates that ccRCC may be more genetically complex than previously thought and provides information that can lead to new ways to investigate individual tumors, with the aim of developing more effective cellular targeted therapies. Copyright © 2012 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                9216904
                2419
                Nat Genet
                Nat. Genet.
                Nature genetics
                1061-4036
                1546-1718
                29 May 2012
                10 June 2012
                02 October 2013
                : 44
                : 7
                : 751-759
                Affiliations
                [1 ]Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX
                [2 ]Department of Developmental Biology, UT Southwestern Medical Center, Dallas, TX
                [3 ]Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX
                [4 ]Illumina Inc., San Diego, CA
                [5 ]Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX
                [6 ]Department of Urology, UT Southwestern Medical Center, Dallas, TX
                [7 ]Department of Clinical genetics, UT Southwestern Medical Center, Dallas, TX
                [8 ]Department of Pathology, UT Southwestern Medical Center, Dallas, TX
                [9 ]Illumina Cambridge Ltd., Essex, UK
                Author notes
                []To whom correspondence should be addressed. Contact: James Brugarolas, MD, PhD, Phone: 214-648-4059, Fax: 214-648-1960, james.brugarolas@ 123456utsouthwestern.edu
                Article
                NIHMS377160
                10.1038/ng.2323
                3788680
                22683710

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                Funding
                Funded by: National Cancer Institute : NCI
                Award ID: R01 CA129387 || CA
                Funded by: National Cancer Institute : NCI
                Award ID: P30 CA142543 || CA
                Categories
                Article

                Genetics

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