Germline BAP1 mutations predispose to malignant mesothelioma
Joseph R. Testa,Mitchell Cheung,Jianming Pei,Jennifer E. Below,Yinfei Tan,Eleonora Sementino,Nancy J. Cox,A. Umran Dogan,A. Umran Dogan,Harvey I. Pass,Sandra Trusa,Mary Hesdorffer,Masaki Nasu,Amy Powers,Zeyana Rivera,Sabahattin Cömertpay,Mika Tanji,Giovanni Gaudino,Haining Yang,Michele Carbone +19 more
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TLDR
A BAP1-related cancer syndrome is identified that is characterized by mesothelioma and uveal melanoma, and it is hypothesized that other cancers may also be involved and that mesot helioma predominates upon asbestos exposure.Abstract:
Because only a small fraction of asbestos-exposed individuals develop malignant mesothelioma, and because mesothelioma clustering is observed in some families, we searched for genetic predisposing factors. We discovered germline mutations in the gene encoding BRCA1 associated protein-1 (BAP1) in two families with a high incidence of mesothelioma, and we observed somatic alterations affecting BAP1 in familial mesotheliomas, indicating biallelic inactivation. In addition to mesothelioma, some BAP1 mutation carriers developed uveal melanoma. We also found germline BAP1 mutations in 2 of 26 sporadic mesotheliomas; both individuals with mutant BAP1 were previously diagnosed with uveal melanoma. We also observed somatic truncating BAP1 mutations and aberrant BAP1 expression in sporadic mesotheliomas without germline mutations. These results identify a BAP1-related cancer syndrome that is characterized by mesothelioma and uveal melanoma. We hypothesize that other cancers may also be involved and that mesothelioma predominates upon asbestos exposure. These findings will help to identify individuals at high risk of mesothelioma who could be targeted for early intervention.read more
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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
TL;DR: 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.
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Interplay Between the Cancer Genome and Epigenome
Hui Shen,Peter W. Laird +1 more
TL;DR: The ways in which alterations in the genome and epigenome influence each other and cooperate to promote oncogenic transformation are explored.
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The role of mutations in epigenetic regulators in myeloid malignancies
TL;DR: Recent genetic and functional data implicating mutations in epigenetic modifiers, including tet methylcytosine dioxygenase 2 (TET2), isocitrate dehydrogenase 1 (IDH1), IDH2, additional sex combs-like 1 (ASXL1), enhancer of zeste homologue 2 (EZH2) and DNA methyltransferase 3A (DNMT3A) are discussed.
Journal ArticleDOI
Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations
Raphael Bueno,Eric Stawiski,Leonard D. Goldstein,Steffen Durinck,Assunta De Rienzo,Zora Modrusan,Florian Gnad,Thong T. Nguyen,Bijay S. Jaiswal,Lucian R. Chirieac,Daniele Sciaranghella,Nhien Dao,Corinne E. Gustafson,Kiara J. Munir,Jason A. Hackney,Amitabha Chaudhuri,Ravi Gupta,Joseph Guillory,Karen Toy,Connie Ha,Ying-Jiun Chen,Jeremy Stinson,Subhra Chaudhuri,Na Zhang,Thomas D. Wu,David J. Sugarbaker,Frederic J. de Sauvage,William G. Richards,Somasekar Seshagiri +28 more
TL;DR: Recurrent gene fusions and splice alterations to be frequent mechanisms for inactivation of NF2, BAP1 and SETD2 are found and alterations in Hippo, mTOR, histone methylation, RNA helicase and p53 signaling pathways in MPMs are identified.
Journal ArticleDOI
ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression.
Omar Abdel-Wahab,Mazhar Adli,Lindsay M. LaFave,Jie Gao,Todd Hricik,Alan H. Shih,Suveg Pandey,Jay P. Patel,Young Rock Chung,Richard Koche,Fabiana Perna,Xinyang Zhao,Jordan E. Taylor,Christopher Y. Park,Martin Carroll,Ari Melnick,Stephen D. Nimer,Jacob D. Jaffe,Iannis Aifantis,Bradley E. Bernstein,Ross L. Levine,Ross L. Levine +21 more
TL;DR: It is identified that ASXL1 mutations result in loss of polycomb repressive complex 2 (PRC2)-mediated histone H3 lysine 27 (H3K27) tri-methylation, and that loss of AS XL1 in vivo collaborates with NRASG12D to promote myeloid leukemogenesis.
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TL;DR: The Phase II HapMap is described, which characterizes over 3.1 million human single nucleotide polymorphisms genotyped in 270 individuals from four geographically diverse populations and includes 25–35% of common SNP variation in the populations surveyed, and increased differentiation at non-synonymous, compared to synonymous, SNPs is demonstrated.
Journal ArticleDOI
Frequent Mutation of BAP1 in Metastasizing Uveal Melanomas
J. William Harbour,Michael D. Onken,Elisha D.O. Roberson,Shenghui Duan,Li Cao,Lori A. Worley,Katie A. Matatall,Cynthia Helms,Anne M. Bowcock +8 more
TL;DR: Exome capture coupled with massively parallel sequencing is used to search for metastasis-related mutations in highly metastatic uveal melanomas of the eye and implicate loss of BAP1 in uveAL melanoma metastasis and suggest that the BAP 1 pathway may be a valuable therapeutic target.
Journal ArticleDOI
Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms and rare CNVs.
Joshua M. Korn,Finny G Kuruvilla,Steven A. McCarroll,Steven A. McCarroll,Alec Wysoker,James Nemesh,Simon Cawley,Earl Hubbell,Jim Veitch,Patrick J Collins,Katayoon Darvishi,Charles Lee,Marcia M. Nizzari,Stacey Gabriel,Shaun Purcell,Shaun Purcell,Mark J. Daly,Mark J. Daly,David Altshuler +18 more
TL;DR: Birdsuite is presented, a four-stage analytical framework instantiated in software for deriving integrated and mutually consistent copy number and SNP genotypes that more accurately depict the underlying sequence of each individual, reducing the rate of apparent mendelian inconsistencies.
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