Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer

被引：1112

作者：

Peifer, Martin ^{[1
,2
,3
]}

Fernandez-Cuesta, Lynnette ^{[1
,2
,3
]}

Sos, Martin L. ^{[1
,2
,3
,4
,5
]}

George, Julie ^{[1
,2
,3
]}

Seidel, Danila ^{[1
,2
,3
,6
]}

Kasper, Lawryn H. ^{[7
]}

Plenker, Dennis ^{[1
,2
,3
]}

Leenders, Frauke ^{[1
,2
,3
,6
]}

Sun, Ruping ^{[8
]}

Zander, Thomas ^{[1
,2
,3
,4
,5
]}

Menon, Roopika ^{[9
]}

Koker, Mirjam ^{[1
,2
,3
]}

Dahmen, Ilona ^{[1
,2
,3
]}

Mueller, Christian ^{[1
,2
,3
]}

Di Cerbo, Vincenzo ^{[10
]}

Schildhaus, Hans-Ulrich ^{[11
]}

Altmueller, Janine ^{[12
]}

Baessmann, Ingelore ^{[12
]}

Becker, Christian ^{[12
]}

de Wilde, Bram ^{[13
]}

Vandesompele, Jo ^{[13
]}

Boehm, Diana ^{[9
]}

Ansen, Sascha ^{[4
,5
]}

Gabler, Franziska ^{[2
,3
]}

Wilkening, Ines ^{[2
,3
]}

Heynck, Stefanie ^{[2
,3
]}

Heuckmann, Johannes M. ^{[1
,2
,3
]}

Lu, Xin ^{[1
,2
,3
]}

Carter, Scott L. ^{[14
]}

Cibulskis, Kristian ^{[14
]}

Banerji, Shantanu ^{[14
]}

Getz, Gad ^{[14
]}

Park, Kwon-Sik ^{[15
,16
]}

Rauh, Daniel ^{[17
]}

Gruetter, Christian ^{[17
]}

Fischer, Matthias ^{[18
,19
]}

Pasqualucci, Laura ^{[20
,21
]}

Wright, Gavin ^{[22
]}

Wainer, Zoe ^{[22
]}

Russell, Prudence ^{[23
]}

Petersen, Iver ^{[24
]}

Chen, Yuan ^{[24
]}

Stoelben, Erich ^{[25
]}

Ludwig, Corinna ^{[25
]}

Schnabel, Philipp ^{[26
]}

Hoffmann, Hans ^{[27
]}

Muley, Thomas ^{[27
]}

Brockmann, Michael ^{[28
]}

Engel-Riedel, Walburga ^{[25
]}

Muscarella, Lucia A. ^{[29
]}

机构：

[1] Univ Cologne, Dept Translat Genom, D-50931 Cologne, Germany

[2] Univ Cologne, Max Planck Inst Neurol Res, Klaus Joachim Zulch Labs, Max Planck Soc, D-50931 Cologne, Germany

[3] Univ Cologne, Fac Med, D-50931 Cologne, Germany

[4] Univ Cologne, Dept Internal Med 1, D-50931 Cologne, Germany

[5] Univ Cologne, Ctr Integrated Oncol Koln Bonn, D-50931 Cologne, Germany

[6] Univ Cologne, Lab Translat Canc Genom, Ctr Integrated Oncol Kolm Bonn, D-50931 Cologne, Germany

[7] St Jude Childrens Res Hosp, Dept Biochem, Memphis, TN 38105 USA

[8] Max Planck Inst Mol Genet, D-14195 Berlin, Germany

[9] Univ Hosp Bonn, Inst Prostate Canc Res, Inst Pathol, Bonn, Germany

[10] Max Planck Inst Immunobiol & Epigenet, Freiburg, Germany

[11] Univ Cologne, Dept Pathol, Cologne, Germany

[12] Univ Cologne, Cologne Ctr Genom, D-50931 Cologne, Germany

[13] Univ Ghent, Ctr Med Genet, B-9000 Ghent, Belgium

[14] Broad Inst Harvard & MIT, Cambridge, MA USA

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

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

[17] Tech Univ Dortmund, Dept Chem Biol, Dortmund, Germany

[18] Univ Childrens Hosp Cologne, Dept Pediat Oncol & Hematol, Cologne, Germany

[19] Univ Cologne, CMMC, D-50931 Cologne, Germany

[20] Columbia Univ, Inst Canc Genet, New York, NY USA

[21] Columbia Univ, Herbert Irving Comprehens Canc Ctr, New York, NY USA

[22] Univ Melbourne, Dept Surg, St Vincents Hosp, Melbourne, Vic, Australia

[23] St Vincents Hosp, Dept Pathol, Melbourne, Vic, Australia

[24] Univ Jena, Jena Univ Hosp, Inst Pathol, Jena, Germany

[25] Kliniken Stadt Koln, Lungenklin Merheim, Dept Thorac Surg, Cologne, Germany

[26] Heidelberg Univ, Inst Pathol, D-6900 Heidelberg, Germany

[27] Thoraxklin Heidelberg, Dept Thorac Surg, Heidelberg, Germany

[28] Hosp Merheim, Dept Pathol, Kliniken Stadt Koln, Cologne, Germany

[29] Ist Ricovero & Cura Carattere Sci IRCCS Casa Soll, Lab Oncol, San Giovanni Rotondo, Italy

[30] Univ Groningen, Univ Med Ctr Groningen, Dept Pulm Dis, NL-9713 AV Groningen, Netherlands

[31] Univ Med Ctr Groningen, Dept Pathol, NL-9713 AV Groningen, Netherlands

[32] Vrije Univ Amsterdam, Med Ctr, Dept Pathol, Amsterdam, Netherlands

[33] Vrije Univ Amsterdam, Med Ctr, Dept Pulm Dis, Amsterdam, Netherlands

[34] Osped Civile, Dept Med Oncol, Livorno, Italy

[35] Univ Hosp Bologna, Dept Haematol & Oncol Sci, Bologna, Italy

[36] Univ Liverpool, Roy Castle Lung Canc Res Programme, Canc Res Ctr, Liverpool L69 3BX, Merseyside, England

[37] Oslo Univ Hosp, Rikshosp, Dept Thorac Surg, Oslo, Norway

[38] Univ Oslo, Fac Med, Inst Clin Med, Oslo, Norway

[39] Oslo Univ Hosp, Norwegian Radium Hosp, Dept Oncol, Oslo, Norway

[40] Oslo Univ Hosp, Norwegian Radium Hosp, Dept Pathol, Oslo, Norway

[41] Inst Pathol Bad Berka, Bad Berka, Germany

[42] Univ Jena, Dept Internal Med 2, Jena Univ Hosp, Jena, Germany

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

[44] Univ Zurich Hosp, Div Thorac Surg, CH-8091 Zurich, Switzerland

[45] Peter MacCallum Canc Ctr, Dept Haematol & Med Oncol, Melbourne, Vic, Australia

[46] Inst Gustave Roussy, Dept Med, Phase Unit 1, Villejuif, France

[47] Inst Mutualiste Montsouris, France Serv Anat Pathol, Paris, France

[48] Univ Grenoble 1, Dept Pathol, Grenoble, France

[49] Univ Grenoble 1, Inst Albert Bonniot, INSERM U823, Grenoble, France

[50] Univ Cologne, Inst Legal Med, D-50931 Cologne, Germany

来源：

NATURE GENETICS | 2012年 / 44卷 / 10期

基金：

美国国家卫生研究院;

关键词：

FREQUENT MUTATION; EGFR MUTATIONS; MOUSE MODEL; E-CADHERIN; GENE; P53; CBP; ACETYLATION; SIGNATURES; FUSIONS;

D O I：

10.1038/ng.2396

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Small-cell lung cancer (SCLC) is an aggressive lung tumor subtype with poor prognosis(1-3). We sequenced 29 SCLC exomes, 2 genomes and 15 transcriptomes and found an extremely high mutation rate of 7.4 +/- 1 protein-changing mutations per million base pairs. Therefore, we conducted integrated analyses of the various data sets to identify pathogenetically relevant mutated genes. In all cases, we found evidence for inactivation of TP53 and RB1 and identified recurrent mutations in the CREBBP, EP300 and MLL genes that encode histone modifiers. Furthermore, we observed mutations in PTEN, SLIT2 and EPHA7, as well as focal amplifications of the FGFR1 tyrosine kinase gene. Finally, we detected many of the alterations found in humans in SCLC tumors from Tp53 and Rb1 double knockout mice(4). Our study implicates histone modification as a major feature of SCLC, reveals potentially therapeutically tractable genomic alterations and provides a generalizable framework for the identification of biologically relevant genes in the context of high mutational background.

引用

页码：1104 / +

页数：9

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