Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors

被引：301

作者：

George, Julie ^{[1
]}

Walter, Vonn ^{[2
,3
]}

Peifer, Martin ^{[1
,4
]}

Alexandrov, Ludmil B. ^{[5
,6
,7
]}

Seidel, Danila ^{[1
]}

Leenders, Frauke ^{[1
]}

Maas, Lukas ^{[1
]}

Mueller, Christian ^{[1
]}

Dahmen, Ilona ^{[1
]}

Delhomme, Tiffany M. ^{[8
]}

Ardin, Maude ^{[9
]}

Leblay, Noemie ^{[8
]}

Byrnes, Graham ^{[10
]}

Sun, Ruping ^{[11
]}

De Reynies, Aurelien ^{[12
]}

McLeer-Florin, Anne ^{[13
]}

Bosco, Graziella ^{[1
]}

Malchers, Florian ^{[1
]}

Menon, Roopika ^{[14
]}

Altmuller, Janine ^{[4
,15
,16
]}

Becker, Christian ^{[15
]}

Nurnberg, Peter ^{[4
,15
,17
]}

Achter, Viktor ^{[18
]}

Lang, Ulrich ^{[18
,19
]}

Schneider, Peter M. ^{[20
]}

Bogus, Magdalena ^{[20
]}

Soloway, Matthew G. ^{[2
]}

Wilkerson, Matthew D. ^{[21
]}

Cun, Yupeng ^{[1
,4
]}

McKay, James D. ^{[8
]}

Moro-Sibilot, Denis ^{[22
]}

Brambilla, Christian G. ^{[22
]}

Lantuejoul, Sylvie ^{[23
,24
]}

Lemaitre, Nicolas ^{[23
]}

Soltermann, Alex ^{[25
]}

Weder, Walter ^{[26
]}

Tischler, Verena ^{[25
]}

Brustugun, Odd Terje ^{[27
,28
]}

Lund-Iversen, Marius ^{[29
]}

Helland, Aslaug ^{[26
,27
]}

Solberg, Steinar ^{[30
]}

Ansen, Sascha ^{[31
]}

Wright, Gavin ^{[32
]}

Solomon, Benjamin ^{[33
]}

Roz, Luca ^{[34
]}

Pastorino, Ugo ^{[35
]}

Petersen, Iver ^{[36
]}

Clement, Joachim H. ^{[37
]}

Saenger, Jorg ^{[38
]}

Wolf, Jurgen ^{[31
]}

机构：

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

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

[3] Penn State Milton S Hershey Med Ctr, Dept Biochem & Mol Biol, 500 Univ Dr, Hershey, PA 17033 USA

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

[5] Univ Calif La Jolla, Dept Cellular & Mol Med, San Diego, CA 92093 USA

[6] Univ Calif La Jolla, Dept Bioengn, San Diego, CA 92093 USA

[7] Univ Calif La Jolla, Moores Canc Ctr, San Diego, CA 92093 USA

[8] WHO, IARC, Sect Genet, Genet Canc Susceptibil Grp, F-69008 Lyon, France

[9] WHO, IARC, Sect Mech Carcinogenesis, Mol Mech & Biomarkers Grp, F-69008 Lyon, France

[10] WHO, IARC, Sect Environm & Radiat, F-69008 Lyon, France

[11] Max Planck Inst Mol Genet, Computat Mol Biol Grp, D-14195 Berlin, Germany

[12] Ligue Natl Canc, Programme Cartes Identite Tumeurs CIT, 14 Rue Corvisart, F-75013 Paris, France

[13] CHU Grenoble Alpes, UGA, CNRS, INSERM,U1209, Grenoble, France

[14] NEO New Oncol GmbH, D-51105 Cologne, Germany

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

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

[17] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, D-50931 Cologne, Germany

[18] Univ Cologne, Comp Ctr, D-50931 Cologne, Germany

[19] Univ Cologne, Dept Informat, D-50931 Cologne, Germany

[20] Univ Hosp Cologne, Inst Legal Med, D-50823 Cologne, Germany

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

[22] Univ Grenoble Alpes, CHUGA Grenoble, IAB, INSERM,U1209,CS10217, F-38043 Grenoble, France

[23] Univ Grenoble Alpes, CHUGA, Dept Pathol, IAB,INSERM U 1209,CS10217, Grenoble, France

[24] UNICANCER, Ctr Leon Berard, Dept Biopathol, F-69008 Lyon, France

[25] Univ Zurich Hosp, Inst Pathol & Mol Pathol, CH-8091 Zurich, Switzerland

[26] Univ Zurich Hosp, Dept Thorac Surg, CH-8091 Zurich, Switzerland

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

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

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

[30] Oslo Univ Hosp, Rikshosp, Dept Thorac Surg, N-0027 Oslo, Norway

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

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

[33] Peter MacCallum Canc Ctr, Dept Haematol & Med Oncol, Melbourne, Vic 3065, Australia

[34] Ist Nazl Tumori, Fdn IRCCS, Dept Expt Oncol & Mol Med, Tumor Genom Unit, Via Venezian 1, I-20133 Milan, Italy

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

[36] Friedrich Schiller Univ, Jena Univ Hosp, Inst Pathol, D-07743 Jena, Germany

[37] Friedrich Schiller Univ, Jena Univ Hosp, Dept Internal Med 2, D-07743 Jena, Germany

[38] Inst Pathol Bad Berka, D-99438 Bad Berka, Germany

[39] Univ Hosp Cologne, Ctr Integrated Oncol Cologne Bonn, Dept Internal Med 1, Gastrointestinal Canc Grp Cologne, D-50823 Cologne, Germany

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

[41] Univ Med Ctr Schleswig Holstein, Pathol, Campus Luebeck, D-23538 Lubeck, Germany

[42] Leibniz Ctr Med & Biosci, Res Ctr Borstel, D-23845 Borstel, Germany

[43] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA

[44] German Canc Consortium DKTK, German Canc Res Ctr, D-69120 Heidelberg, Germany

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

关键词：

MUTATIONAL PROCESSES; SOMATIC MUTATIONS; NONSMALL CELL; GENE; CANCER; EXPRESSION; ADENOCARCINOMAS; CLASSIFICATION; HETEROGENEITY; MICROARRAYS;

D O I：

10.1038/s41467-018-03099-x

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：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Pulmonary large-cell neuroendocrine carcinomas (LCNECs) have similarities with other lung cancers, but their precise relationship has remained unclear. Here we perform a comprehensive genomic (n = 60) and transcriptomic (n = 69) analysis of 75 LCNECs and identify two molecular subgroups: "type I LCNECs" with bi-allelic TP53 and STK11/KEAP1 alterations (37%), and "type II LCNECs" enriched for bi-allelic inactivation of TP53 and RB1 (42%). Despite sharing genomic alterations with adenocarcinomas and squamous cell carcinomas, no transcriptional relationship was found; instead LCNECs form distinct transcriptional subgroups with closest similarity to SCLC. While type I LCNECs and SCLCs exhibit a neuroendocrine profile with ASCL1(high)/DLL3(high)/NOTCHlow, type II LCNECs bear TP53 and RB1 alterations and differ from most SCLC tumors with reduced neuroendocrine markers, a pattern of ASCL1l(ow)/DLL3(low)/NOTCHhigh, and an upregulation of immune-related pathways. In conclusion, LCNECs comprise two molecularly defined subgroups, and distinguishing them from SCLC may allow stratified targeted treatment of high-grade neuroendocrine lung tumors.

引用

页数：13

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