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Comprehensive genomic profiles of small cell lung cancer.
George, Julie; Lim, Jing Shan; Jang, Se Jin; Cun, Yupeng; Ozretic, Luka; Kong, Gu; Leenders, Frauke; Lu, Xin; Fernández-Cuesta, Lynnette; Bosco, Graziella; Müller, Christian; Dahmen, Ilona; Jahchan, Nadine S; Park, Kwon-Sik; Yang, Dian; Karnezis, Anthony N; Vaka, Dedeepya; Torres, Angela; Wang, Maia Segura; Korbel, Jan O; Menon, Roopika; Chun, Sung-Min; Kim, Deokhoon; Wilkerson, Matt; Hayes, Neil; Engelmann, David; Pützer, Brigitte; Bos, Marc; Michels, Sebastian; Vlasic, Ignacija; Seidel, Danila; Pinther, Berit; Schaub, Philipp; Becker, Christian; Altmüller, Janine; Yokota, Jun; Kohno, Takashi; Iwakawa, Reika; Tsuta, Koji; Noguchi, Masayuki; Muley, Thomas; Hoffmann, Hans; Schnabel, Philipp A; Petersen, Iver; Chen, Yuan; Soltermann, Alex; Tischler, Verena; Choi, Chang-min; Kim, Yong-Hee; Massion, Pierre P.
Afiliação
  • George J; Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
  • Lim JS; Departments of Pediatrics and Genetics, Stanford University, Stanford, California 94305, USA.
  • Jang SJ; Department of Pathology and Center for Cancer Genome Discovery, University of Ulsan College of Medicine, Asan Medical Center 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea.
  • Cun Y; Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
  • Ozretic L; Department of Pathology, University Hospital Cologne, 50937 Cologne, Germany.
  • Kong G; Department of Pathology, College of Medicine, Hanyang University. 222 Wangsimniro, Seongdong-gu, Seoul 133-791, Korea.
  • Leenders F; Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
  • Lu X; Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
  • Fernández-Cuesta L; Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
  • Bosco G; Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
  • Müller C; Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
  • Dahmen I; Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
  • Jahchan NS; Departments of Pediatrics and Genetics, Stanford University, Stanford, California 94305, USA.
  • Park KS; Departments of Pediatrics and Genetics, Stanford University, Stanford, California 94305, USA.
  • Yang D; Departments of Pediatrics and Genetics, Stanford University, Stanford, California 94305, USA.
  • Karnezis AN; Vancouver General Hospital, Terry Fox laboratory, Vancouver, British Columbia V5Z 1L3, Canada.
  • Vaka D; Departments of Pediatrics and Genetics, Stanford University, Stanford, California 94305, USA.
  • Torres A; Departments of Pediatrics and Genetics, Stanford University, Stanford, California 94305, USA.
  • Wang MS; European Molecular Biology Laboratory, Genome Biology Unit, 69117 Heidelberg, Germany.
  • Korbel JO; European Molecular Biology Laboratory, Genome Biology Unit, 69117 Heidelberg, Germany.
  • Menon R; Institute of Pathology, Center of Integrated Oncology Cologne-Bonn, University Hospital of Bonn, 53127 Bonn, Germany.
  • Chun SM; Department of Pathology and Center for Cancer Genome Discovery, University of Ulsan College of Medicine, Asan Medical Center 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea.
  • Kim D; Center for Cancer Genome Discovery, University of Ulsan College of Medicine, Asan Medical Center 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea.
  • Wilkerson M; Department of Genetics, Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, North Carolina 27599-7295, USA.
  • Hayes N; UNC Lineberger Comprehensive Cancer Center School of Medicine, University of North Carolina at Chapel Hill, North Carolina 27599-7295, USA.
  • Engelmann D; Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, 18057 Rostock, Germany.
  • Pützer B; Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, 18057 Rostock, Germany.
  • Bos M; Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
  • Michels S; Department I of Internal Medicine, Center of Integrated Oncology Cologne-Bonn, University Hospital Cologne, 50937 Cologne, Germany.
  • Vlasic I; Department of Internal Medicine, University Hospital of Cologne, 50931 Cologne, Germany.
  • Seidel D; Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
  • Pinther B; Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
  • Schaub P; Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
  • Becker C; Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany.
  • Altmüller J; 1] Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany. [2] Institute of Human Genetics, University Hospital Cologne, 50931 Cologne, Germany.
  • Yokota J; 1] Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo 1040045, Japan. [2] Genomics and Epigenomics of Cancer Prediction Program, Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Barcelona 08916, Spain.
  • Kohno T; Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo 1040045, Japan.
  • Iwakawa R; Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo 1040045, Japan.
  • Tsuta K; Department of Pathology and Clinical Laboratories, National Cancer Center Hospital Chuo-ku, Tokyo 1040045, Japan.
  • Noguchi M; Department of Pathology, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan.
  • Muley T; 1] Thoraxklinik at University Hospital Heidelberg, Amalienstrasse 5, 69126 Heidelberg, Germany. [2] Translational Lung Research Center Heidelberg (TLRC-H), Member of German Center for Lung Research (DZL), Amalienstrasse 5, 69126 Heidelberg, Germany.
  • Hoffmann H; Thoraxklinik at University Hospital Heidelberg, Amalienstrasse 5, 69126 Heidelberg, Germany.
  • Schnabel PA; 1] Translational Lung Research Center Heidelberg (TLRC-H), Member of German Center for Lung Research (DZL), Amalienstrasse 5, 69126 Heidelberg, Germany. [2] Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 220, 69120 Heidelberg, Germany.
  • Petersen I; Institute of Pathology, Jena University Hospital, Friedrich-Schiller-University, 07743 Jena, Germany.
  • Chen Y; Institute of Pathology, Jena University Hospital, Friedrich-Schiller-University, 07743 Jena, Germany.
  • Soltermann A; Institute of Surgical Pathology, University Hospital Zürich, 8091 Zürich, Switzerland.
  • Tischler V; Institute of Surgical Pathology, University Hospital Zürich, 8091 Zürich, Switzerland.
  • Choi CM; Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea.
  • Kim YH; Department of Thoracic and Cardiovascular Surgery, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea.
  • Massion PP; Thoracic Program, Vanderbilt-Ingram Cancer Center PRB 640, 2220 Pierce Avenue, Nashville, Tennessee 37232, USA.
Nature ; 524(7563): 47-53, 2015 Aug 06.
Article em En | MEDLINE | ID: mdl-26168399
ABSTRACT
We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Δex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Genoma Humano / Genômica / Carcinoma de Pequenas Células do Pulmão / Neoplasias Pulmonares / Mutação Limite: Animals / Female / Humans / Male Idioma: En Revista: Nature Ano de publicação: 2015 Tipo de documento: Article País de afiliação: Alemanha
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Genoma Humano / Genômica / Carcinoma de Pequenas Células do Pulmão / Neoplasias Pulmonares / Mutação Limite: Animals / Female / Humans / Male Idioma: En Revista: Nature Ano de publicação: 2015 Tipo de documento: Article País de afiliação: Alemanha