YAP1 Expression in SCLC Defines a Distinct Subtype With T-cell-Inflamed Phenotype.
YAP1 Expression in SCLC Defines a Distinct Subtype With T-cell-Inflamed Phenotype.
复制标题
YAP1在SCLC中的表达定义了具有T细胞炎症表型的独特亚型。
DOI：
10.1016/j.jtho.2020.11.006
复制
发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Sica GL
中科院分区：
文献类型：
--
作者：
Owonikoko TK;Dwivedi B;Chen Z;Zhang C;Barwick B;Ernani V;Zhang G;Gilbert-Ross M;Carlisle J;Khuri FR;Curran WJ;Ivanov AA;Fu H;Lonial S;Ramalingam SS;Sun SY;Waller EK;Sica GL
新描述的小细胞肺癌（SCLC）亚型SCLC-A、SCLC-N、SCLC-Y和SCLC-P的临床和生物学意义仍有待确定，SCLC-A、SCLC-N、SCLC-Y和SCLC-P分别由转录因子ASCL 1、NeuroD 1、YAP 1或POU 2F 3的显性表达定义。我们从59个神经内分泌肿瘤的存档肿瘤样本的发现集中生成新的RNA-Seq表达数据，并通过免疫组织化学在99个SCLC病例中生成新的蛋白质表达数据。我们在两个独立的验证集中验证了来自该发现集的发现，该两个独立的验证集由从51个SCLC细胞系和81个原代人SCLC样品生成的RNA-Seq数据组成。我们成功地将71.8%的SCLC和18.5%的类癌病例分类为四种SCLC亚型之一。基因集富集分析（GSEA）的差异表达基因之间的SCLC生存离群值（顶部和底部的十分位数）匹配的临床相关的预后因素，显示IFN-γ反应基因的长期生存者的显着上调。SCLC-Y亚型与IFN-γ应答基因的高表达、经验证的18基因T细胞炎症基因表达谱评分的最高加权评分以及HLA和T细胞受体基因的高表达相关。与广泛期SCLC相比，局限期SCLC中YAP 1蛋白表达更普遍且表达更强烈（30.6%与8.5%; p=0.0058），表明SCLC-Y亚型预后良好。我们在来自SCLC细胞系和肿瘤样品的两个独立验证数据集中复制了SCLC-Y的发炎表型。使用转录信号的SCLC亚型与SCLC-Y亚群相关的炎症表型具有临床相关性。
The clinical and biological significance of the newly described small cell lung cancer (SCLC) subtypes, SCLC-A, SCLC-N, SCLC-Y and SCLC-P, defined respectively by the dominant expression of transcription factors ASCL1, NeuroD1, YAP1 or POU2F3, remain to be established. We generated new RNA-Seq expression data from a discovery set of 59 archival tumor samples of neuroendocrine tumors and new protein expression data by immunohistochemistry in 99 SCLC cases. We validated the findings from this discovery set in two independent validation sets consisting of RNA-Seq data generated from 51 SCLC cell lines and 81 primary human SCLC samples. We successfully classified 71.8% of SCLC and 18.5% of carcinoid cases in our discovery set into one of the four SCLC subtypes. Gene Set Enrichment Analysis (GSEA) for differentially expressed genes between SCLC survival outliers (top and bottom decile) matched for clinically relevant prognostic factors, showed significant upregulation of IFN-γ response genes in long-term survivors. SCLC-Y subtype was associated with high expression of IFN-γ response genes, highest weighted score on a validated 18-gene T-cell inflamed gene expression profile score as well as high expression of HLA and T-cell receptor genes. YAP1 protein expression was more prevalent and more intensely expressed in limited stage versus extensive stage SCLC (30.6% vs. 8.5%; p=0.0058) indicating good prognosis for the SCLC-Y subtype. We replicated the inflamed phenotype of SCLC-Y in the two independent validation datasets from SCLC cell lines and tumor samples. SCLC subtyping using transcriptional signaling hold clinical relevance with the inflamed phenotype associated with SCLC-Y subset.
登录
查看更多内容
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：
10.9
作者：
Danaher P;Warren S;Lu R;Samayoa J;Sullivan A;Pekker I;Wallden B;Marincola FM;Cesano A
通讯作者：
Cesano A
影响因子：
16.6
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
通讯作者：
Thomas RK
影响因子：
5.7
作者：
Horie M;Saito A;Ohshima M;Suzuki HI;Nagase T
通讯作者：
Nagase T
影响因子：
4.4
作者：
Zhu, Zhou;Ihle, Nathan T.;Zarrinkar, Patrick P.
通讯作者：
Zarrinkar, Patrick P.