Comprehensive genomic profiles of small cell lung cancer

被引：1739

作者：

George, Julie ^{[1
]}

Lim, Jing Shan ^{[2
,3
]}

Jang, Se Jin ^{[4
,5
]}

Cun, Yupeng ^{[1
]}

Ozretic, Luka ^{[6
]}

Kong, Gu ^{[7
]}

Leenders, Frauke ^{[1
]}

Lu, Xin ^{[1
]}

Fernandez-Cuesta, Lynnette ^{[1
]}

Bosco, Graziella ^{[1
]}

Mueller, Christian ^{[1
]}

Dahmen, Ilona ^{[1
]}

Jahchan, Nadine S. ^{[2
,3
]}

Park, Kwon-Sik ^{[2
,3
]}

Yang, Dian ^{[2
,3
]}

Karnezis, Anthony N. ^{[8
]}

Vaka, Dedeepya ^{[2
,3
]}

Torres, Angela ^{[2
,3
]}

Wang, Maia Segura ^{[9
]}

Korbel, Jan O. ^{[9
]}

Menon, Roopika ^{[10
]}

Chun, Sung-Min ^{[4
,5
]}

Kim, Deokhoon ^{[11
]}

Wilkerson, Matt ^{[12
]}

Hayes, Neil ^{[13
]}

Engelmann, David ^{[14
]}

Puetzer, Brigitte ^{[14
]}

Bos, Marc ^{[1
]}

Michels, Sebastian ^{[15
]}

Vlasic, Ignacija ^{[16
]}

Seidel, Danila ^{[1
]}

Pinther, Berit ^{[1
]}

Schaub, Philipp ^{[1
]}

Becker, Christian ^{[17
]}

Altmueller, Janine ^{[17
,18
]}

Yokota, Jun ^{[19
,20
]}

Kohno, Takashi ^{[19
]}

Iwakawa, Reika ^{[19
]}

Tsuta, Koji ^{[21
]}

Noguchi, Masayuki ^{[22
]}

Muley, Thomas ^{[23
,24
]}

Hoffmann, Hans ^{[23
]}

Schnabel, Philipp A. ^{[24
,25
]}

Petersen, Iver ^{[26
]}

Chen, Yuan ^{[26
]}

Soltermann, Alex ^{[27
]}

Tischler, Verena ^{[27
]}

Choi, Chang-min ^{[28
]}

Kim, Yong-Hee ^{[29
]}

Massion, Pierre P. ^{[30
]}

机构：

[1] Univ Cologne, Fac Med, Dept Translat Genom, Ctr Integrated Oncol Cologne Bonn, D-50931 Cologne, Germany

[2] Stanford Univ, Dept Pediat, Stanford, CA 94305 USA

[3] Stanford Univ, Dept Genet, Stanford, CA 94305 USA

[4] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Pathol, Seoul 138736, South Korea

[5] Univ Ulsan, Coll Med, Asan Med Ctr, Ctr Canc Genome Discovery, Seoul 138736, South Korea

[6] Univ Hosp Cologne, Dept Pathol, D-50937 Cologne, Germany

[7] Hanyang Univ, Dept Pathol, Coll Med, Seoul 133791, South Korea

[8] Vancouver Gen Hosp, Terry Fox Lab, Vancouver, BC V5Z 1L3, Canada

[9] European Mol Biol Lab, Genome Biol Unit, D-69117 Heidelberg, Germany

[10] Univ Hosp Bonn, Inst Pathol, Ctr Integrated Oncol Cologne Bonn, D-53127 Bonn, Germany

[11] Univ Ulsan, Coll Med, Asan Med Ctr, Ctr Canc Genome Discovery, Seoul 138736, South Korea

[12] Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Genet, Chapel Hill, NC 27599 USA

[13] Univ N Carolina, UNC Lineberger Comprehens Canc Ctr, Sch Med, Chapel Hill, NC 27599 USA

[14] Univ Rostock, Med Ctr, Inst Expt Gene Therapy & Canc Res, D-18057 Rostock, Germany

[15] Univ Hosp Cologne, Ctr Integrated Oncol Cologne Bonn, Dept Internal Med 1, D-50937 Cologne, Germany

[16] Univ Hosp Cologne, Dept Internal Med, D-50931 Cologne, Germany

[17] Univ Cologne, CCG, D-50931 Cologne, Germany

[18] Univ Hosp Cologne, Inst Human Genet, D-50931 Cologne, Germany

[19] Natl Canc Ctr, Res Inst, Div Genome Biol, Chuo Ku, Tokyo 1040045, Japan

[20] Inst Predict & Personalized Med Canc IMPPC, Genom & Epigen Canc Predict Program, Barcelona 08916, Spain

[21] Natl Canc Ctr, Dept Pathol & Clin Labs, Chuo Ku, Tokyo 1040045, Japan

[22] Univ Tsukuba, Fac Med, Dept Pathol, Tsukuba, Ibaraki 3058575, Japan

[23] Univ Heidelberg Hosp, Thoraxklin, D-69126 Heidelberg, Germany

[24] TLRC H, D-69126 Heidelberg, Germany

[25] Heidelberg Univ, Inst Pathol, D-69120 Heidelberg, Germany

[26] Univ Jena, Jena Univ Hosp, Inst Pathol, D-07743 Jena, Germany

[27] Univ Zurich Hosp, Inst Surg Pathol, CH-8091 Zurich, Switzerland

[28] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Oncol, Seoul 138736, South Korea

[29] Univ Ulsan, Coll Med, Dept Thorac & Cardiovasc Surg, Asan Med Ctr, Seoul 138736, South Korea

[30] Vanderbilt Ingram Canc Ctr, Thorac Program, Nashville, TN 37232 USA

[31] Univ Belgrade, Sch Med, Univ Hosp Pulmonol, Clin Ctr Serbia, Belgrade 11000, Serbia

[32] St Vincents Hosp, Peter MacCallum Canc Ctr, Dept Surg, Melbourne, Vic 3065, Australia

[33] St Vincents Hosp, Peter MacCallum Canc Ctr, Dept Pathol, Melbourne, Vic 3065, Australia

[34] Asklepios Fachkliniken, Comprehens Pneumol Ctr Munich, Asklepios Biobank Lungenerkrankungen, D-82131 Munich, Germany

[35] IRCCS Casa Sollievo Sofferenza, Lab Oncol, I-71013 San Giovanni, Rotondo, Italy

[36] Univ Liverpool, Canc Res Ctr, Roy Castle Lung Canc Res Programme, Dept Mol & Clin Canc Med,Inst Translat Med, Liverpool L69 3GA, Merseyside, England

[37] Univ Zagreb, Sch Med, Dept Resp Dis Jordanovac, Univ Hosp Ctr Zagreb, Zagreb 10000, Croatia

[38] Rudjer Boskovic Inst, Lab Translat Med, Zagreb 10000, Croatia

[39] Charite Campus Mitte, Charite Comprehens Canc Ctr, D-10115 Berlin, Germany

[40] Fdn IRCCS Ist Nazl Tumori, Dept Expt Oncol & Mol Med, Tumor Genom Unit, I-20133 Milan, Italy

[41] Fdn IRCCS Ist Nazl Tumori, Dept Surg, Thorac Surg Unit, I-20133 Milan, Italy

[42] Univ Oslo, Fac Med, Inst Clin Med, N-0424 Oslo, Norway

[43] Oslo Univ Hosp, Norwegian Radium Hosp, Dept Oncol, N-0310 Oslo, Norway

[44] Oslo Univ Hosp, Norwegian Radium Hosp, Dept Pathol, N-0310 Oslo, Norway

[45] Vrije Univ Amsterdam Med Ctr, Dept Pathol, NL-1007 MB Amsterdam, Netherlands

[46] Univ Hosp Essen, Dept Med Oncol, West German Canc Ctr, D-45147 Essen, Germany

[47] German Canc Consortium DKTK, D-69120 Heidelberg, Germany

[48] Uppsala Univ, Dept Immunol Genet & Pathol, S-75185 Uppsala, Sweden

[49] Uppsala Univ, Dept Med Sci Resp Allergy & Sleep Res, S-75185 Uppsala, Sweden

[50] Bellvitge Biomed Res Inst IDIBELL, Canc Epigenet & Biol Program PEBC, Genes & Canc Grp, Barcelona 08908, Spain

来源：

NATURE | 2015年 / 524卷 / 7563期

关键词：

CYCLE ARREST; C-KIT; NEUROENDOCRINE; MUTATIONS; NOTCH; CARCINOMA; PATHWAY; GROWTH; GENES; HETEROGENEITY;

D O I：

10.1038/nature14664

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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, TP73Dex2/3. 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.

引用

页码：47 / 53

页数：7

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