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      Recognizing the Continuous Nature of Expression Heterogeneity and Clinical Outcomes in Clear Cell Renal Cell Carcinoma

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          Abstract

          Clear cell renal cell carcinoma (ccRCC) has been previously classified into putative discrete prognostic subtypes by gene expression profiling. To investigate the robustness of these proposed subtype classifications, we evaluated 12 public datasets, together with a new dataset of 265 ccRCC gene expression profiles. Consensus clustering showed unstable subtype and principal component analysis (PCA) showed a continuous spectrum both within and between datasets. Considering the lack of discrete delineation and continuous spectrum observed, we developed a continuous quantitative prognosis score (Continuous Linear Enhanced Assessment of RCC, or CLEAR score). Prognostic performance was evaluated in independent cohorts from The Cancer Genome Atlas (TCGA) (n = 414) and EMBL-EBI (n = 53), CLEAR score demonstrated both superior prognostic estimates and inverse correlation with anti-angiogenic tyrosine-kinase inhibition in comparison to previously proposed discrete subtyping classifications. Inverse correlation with high-dose interleukin-2 outcomes was also observed for the CLEAR score. Multiple somatic mutations (VHL, PBRM1, SETD2, KDM5C, TP53, BAP1, PTEN, MTOR) were associated with the CLEAR score. Application of the CLEAR score to independent expression profiling of intratumoral ccRCC regions demonstrated that average intertumoral heterogeneity exceeded intratumoral expression heterogeneity. Wider investigation of cancer biology using continuous approaches may yield insights into tumor heterogeneity; single cell analysis may provide a key foundation for this approach.

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          Most cited references 10

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          BAP1 loss defines a new class of renal cell carcinoma

          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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            Molecular Stratification of Clear Cell Renal Cell Carcinoma by Consensus Clustering Reveals Distinct Subtypes and Survival Patterns.

            Clear cell renal cell carcinoma (ccRCC) is the predominant RCC subtype, but even within this classification, the natural history is heterogeneous and difficult to predict. A sophisticated understanding of the molecular features most discriminatory for the underlying tumor heterogeneity should be predicated on identifiable and biologically meaningful patterns of gene expression. Gene expression microarray data were analyzed using software that implements iterative unsupervised consensus clustering algorithms to identify the optimal molecular subclasses, without clinical or other classifying information. ConsensusCluster analysis identified two distinct subtypes of ccRCC within the training set, designated clear cell type A (ccA) and B (ccB). Based on the core tumors, or most well-defined arrays, in each subtype, logical analysis of data (LAD) defined a small, highly predictive gene set that could then be used to classify additional tumors individually. The subclasses were corroborated in a validation data set of 177 tumors and analyzed for clinical outcome. Based on individual tumor assignment, tumors designated ccA have markedly improved disease-specific survival compared to ccB (median survival of 8.6 vs 2.0 years, P = 0.002). Analyzed by both univariate and multivariate analysis, the classification schema was independently associated with survival. Using patterns of gene expression based on a defined gene set, ccRCC was classified into two robust subclasses based on inherent molecular features that ultimately correspond to marked differences in clinical outcome. This classification schema thus provides a molecular stratification applicable to individual tumors that has implications to influence treatment decisions, define biological mechanisms involved in ccRCC tumor progression, and direct future drug discovery.
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              Histone methyltransferase gene SETD2 is a novel tumor suppressor gene in clear cell renal cell carcinoma.

              Sporadic clear cell renal cell carcinoma (cRCC) is genetically characterized by the recurrent loss of the short arm of chromosome 3, with a hotspot for copy number loss in the 3p21 region. We applied a method called "gene identification by nonsense-mediated mRNA decay inhibition" to a panel of 10 cRCC cell lines with 3p21 copy number loss to identify biallelic inactivated genes located at 3p21. This revealed inactivation of the histone methyltransferase gene SETD2, located on 3p21.31, as a common event in cRCC cells. SETD2 is nonredundantly responsible for trimethylation of the histone mark H3K36. Consistent with this function, we observed loss or a decrease of H3K36me3 in 7 out of the 10 cRCC cell lines. Identification of missense mutations in 2 out of 10 primary cRCC tumor samples added support to the involvement of loss of SETD2 function in the development of cRCC tumors. Copyright 2010 AACR.
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                Author and article information

                Contributors
                teh.bin.tean@singhealth.com.sg
                mhtan@ibn.a-star.edu.sg
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                4 August 2017
                4 August 2017
                2017
                : 7
                Affiliations
                [1 ]ISNI 0000 0004 0620 9737, GRID grid.418830.6, , Institute of Bioengineering and Nanotechnology, ; 31 Biopolis Way, The Nanos, 138669 Singapore Republic of Singapore
                [2 ]Lucence Diagnostics Pte Ltd, Singapore, Republic of Singapore
                [3 ]ISNI 0000 0004 0385 0924, GRID grid.428397.3, , Cancer Stem Cell Biology Program, Duke-NUS Graduate Medical School, ; 8 College Road, Singapore, 169857 Republic of Singapore
                [4 ]Urologic Consultants, 25 Michigan Street, Suite 3300, Grand Rapids, MI 49503 USA
                [5 ]ISNI 0000 0004 0450 5903, GRID grid.430538.9, Division of Urology, , Spectrum Health Medical Group, ; 4069 Lake Drive SE, Suite 313, Grand Rapids, MI 49546 USA
                [6 ]Western Michigan Urological Associates, 577 Michigan Avenue, Suite 201, Holland, MI 49423 USA
                [7 ]ISNI 0000 0001 1092 3579, GRID grid.267335.6, Department of Urology, Institute of Biomedical Sciences, , Tokushima University Graduate School, ; 3-18-15, Kuramoto-cho, Tokushima, 770-8503 Japan
                [8 ]ISNI 0000 0000 9632 6718, GRID grid.19006.3e, FACS, Institute of Urologic Oncology, Department of Urology, David Geffen School of Medicine, , University of California Los Angeles, ; 66-118 Center for Health Sciences Box 951738, Los Angeles, CA 90095 USA
                [9 ]ISNI 0000 0001 2152 9905, GRID grid.50956.3f, Division of Urology, , Cedars-Sinai Medical Center, ; 8635W. Third Street, Suite 1070, Los Angeles, CA 90048 USA
                [10 ]ISNI 0000 0001 2160 8953, GRID grid.413103.4, Vattikuti Urology Institute, , Henry Ford Hospital, ; 2799W. Grand Blvd, Detroit, MI USA
                [11 ]ISNI 0000 0001 0304 893X, GRID grid.5072.0, Department of Urology, , The Royal Marsden NHS Foundation Trust, ; 203 Fulham Road, London, SW3 6JJ UK
                [12 ]ISNI 0000 0001 1271 4623, GRID grid.18886.3f, , The Institute of Cancer Research, ; 123 Old Brompton Road, London, SW7 3RP UK
                [13 ]ISNI 0000 0004 0620 9745, GRID grid.410724.4, Laboratory of Cancer Epigenome, , National Cancer Centre Singapore, ; 11 Hospital Drive, Singapore, 169610 Republic of Singapore
                [14 ]ISNI 0000 0001 2180 6431, GRID grid.4280.e, Cancer Science Institute of Singapore, , National University of Singapore, ; 14 Medical Drive, #12-01, Singapore, 117599 Republic of Singapore
                [15 ]ISNI 0000 0004 0620 9745, GRID grid.410724.4, Division of Medical Oncology, , National Cancer Centre Singapore, ; 11 Hospital Drive, Singapore, 169610 Republic of Singapore
                [16 ]MRL IT, MSD International GmbH (Singapore Branch), 1 Fusionopolis Place, #06-10/07-18, Galaxis, Singapore, 138522 Republic of Singapore
                Article
                7191
                10.1038/s41598-017-07191-y
                5544702
                28779136
                © The Author(s) 2017

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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