Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors.
Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors.
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DOI：
10.1038/s41467-018-03099-x
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发表时间：
2018-03-13
影响因子：
16.6
通讯作者：
Thomas RK
中科院分区：
文献类型：
--
作者：
George J;Walter V;Peifer M;Alexandrov LB;Seidel D;Leenders F;Maas L;Müller C;Dahmen I;Delhomme TM;Ardin M;Leblay N;Byrnes G;Sun R;De Reynies A;McLeer-Florin A;Bosco G;Malchers F;Menon R;Altmüller J;Becker C;Nürnberg P;Achter V;Lang U;Schneider PM;Bogus M;Soloway MG;Wilkerson MD;Cun Y;McKay JD;Moro-Sibilot D;Brambilla CG;Lantuejoul S;Lemaitre N;Soltermann A;Weder W;Tischler V;Brustugun OT;Lund-Iversen M;Helland Å;Solberg S;Ansén S;Wright G;Solomon B;Roz L;Pastorino U;Petersen I;Clement JH;Sänger J;Wolf J;Vingron M;Zander T;Perner S;Travis WD;Haas SA;Olivier M;Foll M;Büttner R;Hayes DN;Brambilla E;Fernandez-Cuesta L;Thomas RK
肺大细胞神经内分泌癌(LCNECs)与其他肺癌有相似之处，但它们的确切关系尚不清楚。在这里，我们对75个LCNEC进行了全面的基因组分析(n = 60)和转录学分析(n = 69)，并确定了两个分子亚群：具有TP53和STK11/Keap1双等位基因改变的I型LCNECs(37%)和富含TP53和RB1双等位基因失活的II型LCNECs(42%)。尽管与腺癌和鳞癌有相同的基因组改变，但没有发现转录关系；相反，LCNEC形成了与小细胞肺癌最相似的不同转录亚群。虽然I型LCNECs和SCLC表现出ASCL1High/DLL3High/NOTCHlow的神经内分泌特征，但II型LCNECs携带TP53和RB1改变，不同于大多数小细胞肺癌肿瘤的神经内分泌标志物减少，ASCL1low/DLL3low/NOTCHHigh的模式，以及免疫相关途径的上调。总之，LCNECs包括两个分子定义的亚群，将它们与小细胞肺癌区分开来可能允许对高级别神经内分泌肺肿瘤进行分层靶向治疗。大细胞神经内分泌肺癌(LCNEC)的分子本质尚不清楚。在这里，作者表明LCNECs代表了肺癌中一个独特的转录亚群，包括两个分子亚群，I型(TP53和STK11/Keap1改变)和II型(TP53和RB1失活)。
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 ASCL1high/DLL3high/NOTCHlow, type II LCNECs bear TP53 and RB1 alterations and differ from most SCLC tumors with reduced neuroendocrine markers, a pattern of ASCL1low/DLL3low/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. The molecular nature of large-cell neuroendocrine lung carcinomas (LCNEC) has remained unclear. Here, the authors show LCNECs represent a distinct transcriptional subgroup among lung cancers and comprise two molecular subgroups, type I (TP53 and STK11/KEAP1 alterations) and type II (TP53 and RB1 inactivation).
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影响因子：
8.8
作者：
Borromeo MD;Savage TK;Kollipara RK;He M;Augustyn A;Osborne JK;Girard L;Minna JD;Gazdar AF;Cobb MH;Johnson JE
通讯作者：
Johnson JE
影响因子：
8
作者：
Chen F;Zhang Y;Parra E;Rodriguez J;Behrens C;Akbani R;Lu Y;Kurie JM;Gibbons DL;Mills GB;Wistuba II;Creighton CJ
通讯作者：
Creighton CJ
影响因子：
16.6
作者：
Fernandez-Cuesta, Lynnette;Peifer, Martin;Lu, Xin;Sun, Ruping;Ozretic, Luka;Seidel, Danila;Zander, Thomas;Leenders, Frauke;George, Julie;Mueller, Christian;Dahmen, Ilona;Pinther, Berit;Bosco, Graziella;Konrad, Kathryn;Altmueller, Janine;Nuernberg, Peter;Achter, Viktor;Lang, Ulrich;Schneider, Peter M.;Bogus, Magdalena;Soltermann, Alex;Brustugun, Odd Terje;Helland, Aslaug;Solberg, Steinar;Lund-Iversen, Marius;Ansen, Sascha;Stoelben, Erich;Wright, Gavin M.;Russell, Prudence;Wainer, Zoe;Solomon, Benjamin;Field, John K.;Hyde, Russell;Davies, Michael P. A.;Heukamp, Lukas C.;Petersen, Iver;Perner, Sven;Lovly, Christine M.;Cappuzzo, Federico;Travis, William D.;Wolf, Juergen;Vingron, Martin;Brambilla, Elisabeth;Haas, Stefan A.;Buettner, Reinhard;Thomas, Roman K.
通讯作者：
Thomas, Roman K.
影响因子：
4
作者：
Alexandrov, Ludmil B.;Stratton, Michael R.
通讯作者：
Stratton, Michael R.
影响因子：
5.8
作者：
Dabney, AR
通讯作者：
Dabney, AR