BAP1 loss defines a new class of renal cell carcinoma
Samuel Peña-Llopis,Silvia Vega-Rubin-de-Celis,Silvia Vega-Rubin-de-Celis,Arnold Liao,Nan Leng,Andrea Pavia-Jimenez,Andrea Pavia-Jimenez,Shanshan Wang,Shanshan Wang,Toshinari Yamasaki,Toshinari Yamasaki,Leah Zhrebker,Leah Zhrebker,Sharanya Sivanand,Sharanya Sivanand,Patrick Spence,Patrick Spence,Lisa N. Kinch,Tina Hambuch,Suneer Jain,Yair Lotan,Vitaly Margulis,Arthur I. Sagalowsky,Pia Banerji Summerour,Wareef Kabbani,S. W Wendy Wong,Nick V. Grishin,Marc Laurent,Xian Jin Xie,Christian D. Haudenschild,Mark T. Ross,David R. Bentley,Payal Kapur,James Brugarolas +33 more
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TLDR
The results establish the foundation for an integrated pathological and molecular genetic classification of RCC, paving the way for subtype-specific treatments exploiting genetic vulnerabilities.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. The BAP1 protein, 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 deubiquitination of monoubiquitinated histone 2A lysine 119 (H2AK119ub1). BAP1 loss sensitizes RCC cells in vitro to genotoxic stress. Notably, mutations in BAP1 and PBRM1 anticorrelate in tumors (P = 3 × 10(-5)), [corrected] 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.read more
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Signatures of mutational processes in human cancer
Ludmil B. Alexandrov,Serena Nik-Zainal,Serena Nik-Zainal,David C. Wedge,Samuel Aparicio,Sam Behjati,Sam Behjati,Andrew V. Biankin,Graham R. Bignell,Niccolo Bolli,Niccolo Bolli,Åke Borg,Anne Lise Børresen-Dale,Anne Lise Børresen-Dale,Sandrine Boyault,Birgit Burkhardt,Adam Butler,Carlos Caldas,Helen Davies,Christine Desmedt,Roland Eils,Jorunn E. Eyfjord,John A. Foekens,Mel Greaves,Fumie Hosoda,Barbara Hutter,Tomislav Ilicic,Sandrine Imbeaud,Sandrine Imbeaud,Marcin Imielinsk,Natalie Jäger,David T. W. Jones,David T. Jones,Stian Knappskog,Stian Knappskog,Marcel Kool,Sunil R. Lakhani,Carlos López-Otín,Sancha Martin,Nikhil C. Munshi,Nikhil C. Munshi,Hiromi Nakamura,Paul A. Northcott,Marina Pajic,Elli Papaemmanuil,Angelo Paradiso,John V. Pearson,Xose S. Puente,Keiran Raine,Manasa Ramakrishna,Andrea L. Richardson,Andrea L. Richardson,Julia Richter,Philip Rosenstiel,Matthias Schlesner,Ton N. Schumacher,Paul N. Span,Jon W. Teague,Yasushi Totoki,Andrew Tutt,Rafael Valdés-Mas,Marit M. van Buuren,Laura van ’t Veer,Anne Vincent-Salomon,Nicola Waddell,Lucy R. Yates,Icgc PedBrain,Jessica Zucman-Rossi,Jessica Zucman-Rossi,P. Andrew Futreal,Ultan McDermott,Peter Lichter,Matthew Meyerson,Matthew Meyerson,Sean M. Grimmond,Reiner Siebert,Elias Campo,Tatsuhiro Shibata,Stefan M. Pfister,Stefan M. Pfister,Peter J. Campbell,Peter J. Campbell,Peter J. Campbell,Michael R. Stratton,Michael R. Stratton +84 more
TL;DR: It is shown that hypermutation localized to small genomic regions, ‘kataegis’, is found in many cancer types, and this results reveal the diversity of mutational processes underlying the development of cancer.
Journal ArticleDOI
Mutational landscape and significance across 12 major cancer types
Cyriac Kandoth,Michael D. McLellan,Fabio Vandin,Kai Ye,Beifang Niu,Charles Lu,Mingchao Xie,Qunyuan Zhang,Joshua F. McMichael,Matthew A. Wyczalkowski,Mark D.M. Leiserson,Christopher A. Miller,John S. Welch,Matthew J. Walter,Michael C. Wendl,Timothy J. Ley,Richard K. Wilson,Benjamin J. Raphael,Li Ding +18 more
TL;DR: Data and analytical results for point mutations and small insertions/deletions from 3,281 tumours across 12 tumour types are presented as part of the TCGA Pan-Cancer effort, and clinical association analysis identifies genes having a significant effect on survival.
Journal ArticleDOI
Renal cell carcinoma.
James J. Hsieh,Mark P. Purdue,Sabina Signoretti,Charles Swanton,Laurence Albiges,Manuela Schmidinger,Daniel Y. Heng,James Larkin,Vincenzo Ficarra +8 more
TL;DR: An overview of the biology of RCC, with a focus on ccRCC, as well as updates to complement the current clinical guidelines and an outline of potential future directions for RCC research and therapy are provided.
Journal ArticleDOI
Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing
Marco Gerlinger,Stuart Horswell,James Larkin,Andrew Rowan,Max Salm,Ignacio Varela,Rosalie Fisher,Nicholas McGranahan,Nicholas Matthews,Claudio R. Santos,Pierre Martinez,Benjamin Phillimore,Sharmin Begum,Adam Rabinowitz,Bradley Spencer-Dene,Sakshi Gulati,Paul A. Bates,Gordon Stamp,Lisa Pickering,Martin Gore,David Nicol,Steven Hazell,P. Andrew Futreal,Aengus Stewart,Charles Swanton,Charles Swanton +25 more
TL;DR: It was found that 73–75% of identified ccRCC driver aberrations were subclonal, confounding estimates of driver mutation prevalence, and the proportion of C>T transitions at CpG sites increased during tumor progression.
Journal ArticleDOI
Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy
Cigall Kadoch,Diana C. Hargreaves,Courtney Hodges,Laura Elias,Lena Ho,Jeff Ranish,Gerald R. Crabtree +6 more
TL;DR: It is demonstrated that mSWI/SNF is the most frequently mutated chromatin-regulatory complex (CRC) in human cancer, exhibiting a broad mutation pattern, similar to that of TP53, and proper functioning of polymorphic BAF complexes may constitute a major mechanism of tumor suppression.
References
More filters
Journal ArticleDOI
Controlling the false discovery rate: a practical and powerful approach to multiple testing
Yoav Benjamini,Yosef Hochberg +1 more
TL;DR: In this paper, a different approach to problems of multiple significance testing is presented, which calls for controlling the expected proportion of falsely rejected hypotheses -the false discovery rate, which is equivalent to the FWER when all hypotheses are true but is smaller otherwise.
Journal ArticleDOI
The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling
TL;DR: The SWISS-MODEL workspace is a web-based integrated service dedicated to protein structure homology modelling that assists and guides the user in building protein homology models at different levels of complexity.
Journal ArticleDOI
Intratumor heterogeneity and branched evolution revealed by multiregion sequencing.
Marco Gerlinger,Andrew Rowan,Stuart Horswell,James Larkin,David Endesfelder,Eva Grönroos,Pierre Martinez,Nicholas Matthews,Aengus Stewart,Patrick S. Tarpey,Ignacio Varela,Benjamin Phillimore,Sharmin Begum,Neil Q. McDonald,Adam Butler,David T. Jones,Keiran Raine,Calli Latimer,Claudio R. Santos,Mahrokh Nohadani,Aron Charles Eklund,Bradley Spencer-Dene,Graham Clark,Lisa Pickering,Gordon Stamp,Martin Gore,Zoltan Szallasi,Zoltan Szallasi,Julian Downward,P. Andrew Futreal,Charles Swanton +30 more
TL;DR: Intratumor heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor-biopsy samples and may present major challenges to personalized-medicine and biomarker development.
Journal ArticleDOI
Tests for comparing elements of a correlation matrix.
TL;DR: This article reviewed the literature on such tests, pointed out some statistics that should be avoided, and presented a variety of techniques that can be used safely with medium to large samples, and several illustrative numerical examples are provided.
Journal ArticleDOI
Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths.
TL;DR: Overall cancer death rates decreased in all racial/ethnic groups in both men and women from 1998 through 2007, with the exception of American Indian/Alaska Native women, in whom rates were stable.
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