Inactivation of Hippo pathway characterizes a poor-prognosis subtype of esophageal cancer.
Inactivation of Hippo pathway characterizes a poor-prognosis subtype of esophageal cancer.
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Hippo 通路失活是食管癌预后不良亚型的特征
DOI：
10.1172/jci.insight.155218
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发表时间：
2022-08-22
期刊：
影响因子：
8
通讯作者：
Fu, Jianhua
中科院分区：
文献类型：
--
作者：
Mai, Zihang;Yuan, Jianye;Yang, Hong;Fang, Shuogui;Xie, Xiuying;Wang, Xinye;Xie, Jiaxin;Wen, Jing;Fu, Jianhua
识别反映不同预后和治疗反应的分子亚型，特别是免疫检查点抑制物(ICIS)在食管鳞癌(ESCC)中的作用，对于治疗决策至关重要。我们对201名ESCC患者进行了靶向测序，以发现基因亚型，并通过多个数据集验证我们的发现。我们鉴定了3个驱动基因(FCGBP、GRIN2B和Fry)，Fry的反复截断突变削弱了其抑瘤功能，促进了肿瘤的增殖。一个3基因突变标记(FAT1、FAT3和Fry)识别了一个名为“Fat/Fry”的分子亚型，该亚型与河马途径相关的突变频繁。在多个ESCC队列中，FAT/Fry亚型患者的预后比WT组患者差。转录组分析表明，FAT/Fry亚型的特征是河马途径失活、低氧、化疗耐药、CD8+T细胞和激活的DC的高渗透，以及类似于癌症应答者的转录组。此外，3基因标志预示着接受ICIS治疗的患者有更好的生存，部分原因是它与肿瘤突变负荷和新抗原负荷呈正相关。3基因标志是识别脂肪/脂肪分子亚型、评估预后和选择食管鳞癌ICIS潜在受益者的生物标志物。
Identification of molecular subtypes that reflect different prognoses and treatment responses, especially immune checkpoint inhibitors (ICIs) in esophageal squamous cell carcinoma (ESCC), is essential for treatment decisions. We performed targeted sequencing in 201 patients with ESCC to discover genetic subtypes and validate our findings via multiple data sets. We identified 3 driver genes (FCGBP, GRIN2B, and FRY), and recurrent truncating mutations in FRY impaired its tumor-suppressive function and promoted tumor proliferation. A 3-gene mutation signature (FAT1, FAT3, and FRY) recognized a molecular subtype named “FAT/FRY” with frequent Hippo pathway–related mutations. In multiple ESCC cohorts, the patients with the FAT/FRY subtype had poorer prognosis than did patients in the WT group. Transcriptome analysis indicated that the FAT/FRY subtype was characterized by inactivation of the Hippo pathway, hypoxia, chemoresistance, higher infiltration of CD8+ T cells and activated DCs, and a transcriptome similar to that of cancer responders. Furthermore, the 3-gene signature predicted better survival for patients treated with ICIs, partially explained by its positive correlation with the tumor mutation burden and neoantigen burden. The 3-gene signature is a biomarker to recognize the FAT/FRY molecular subtype, evaluate prognosis, and select potential beneficiaries of ICIs in ESCC.
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影响因子：
64.8
作者：
Cancer Genome Atlas Research Network;Analysis Working Group: Asan University;BC Cancer Agency;Brigham and Women’s Hospital;Broad Institute;Brown University;Case Western Reserve University;Dana-Farber Cancer Institute;Duke University;Greater Poland Cancer Centre;Harvard Medical School;Institute for Systems Biology;KU Leuven;Mayo Clinic;Memorial Sloan Kettering Cancer Center;National Cancer Institute;Nationwide Children’s Hospital;Stanford University;University of Alabama;University of Michigan;University of North Carolina;University of Pittsburgh;University of Rochester;University of Southern California;University of Texas MD Anderson Cancer Center;University of Washington;Van Andel Research Institute;Vanderbilt University;Washington University;Genome Sequencing Center: Broad Institute;Washington University in St. Louis;Genome Characterization Centers: BC Cancer Agency;Broad Institute;Harvard Medical School;Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University;University of North Carolina;University of Southern California Epigenome Center;University of Texas MD Anderson Cancer Center;Van Andel Research Institute;Genome Data Analysis Centers: Broad Institute;Brown University:;Harvard Medical School;Institute for Systems Biology;Memorial Sloan Kettering Cancer Center;University of California Santa Cruz;University of Texas MD Anderson Cancer Center;Biospecimen Core Resource: International Genomics Consortium;Research Institute at Nationwide Children’s Hospital;Tissue Source Sites: Analytic Biologic Services;Asan Medical Center;Asterand Bioscience;Barretos Cancer Hospital;BioreclamationIVT;Botkin Municipal Clinic;Chonnam National University Medical School;Christiana Care Health System;Cureline;Duke University;Emory University;Erasmus University;Indiana University School of Medicine;Institute of Oncology of Moldova;International Genomics Consortium;Invidumed;Israelitisches Krankenhaus Hamburg;Keimyung University School of Medicine;Memorial Sloan Kettering Cancer Center;National Cancer Center Goyang;Ontario Tumour Bank;Peter MacCallum Cancer Centre;Pusan National University Medical School;Ribeirão Preto Medical School;St. Joseph’s Hospital &Medical Center;St. Petersburg Academic University;Tayside Tissue Bank;University of Dundee;University of Kansas Medical Center;University of Michigan;University of North Carolina at Chapel Hill;University of Pittsburgh School of Medicine;University of Texas MD Anderson Cancer Center;Disease Working Group: Duke University;Memorial Sloan Kettering Cancer Center;National Cancer Institute;University of Texas MD Anderson Cancer Center;Yonsei University College of Medicine;Data Coordination Center: CSRA Inc.;Project Team: National Institutes of Health
通讯作者：
Project Team: National Institutes of Health
影响因子：
28.2
作者：
Chen PL;Roh W;Reuben A;Cooper ZA;Spencer CN;Prieto PA;Miller JP;Bassett RL;Gopalakrishnan V;Wani K;De Macedo MP;Austin-Breneman JL;Jiang H;Chang Q;Reddy SM;Chen WS;Tetzlaff MT;Broaddus RJ;Davies MA;Gershenwald JE;Haydu L;Lazar AJ;Patel SP;Hwu P;Hwu WJ;Diab A;Glitza IC;Woodman SE;Vence LM;Wistuba II;Amaria RN;Kwong LN;Prieto V;Davis RE;Ma W;Overwijk WW;Sharpe AH;Hu J;Futreal PA;Blando J;Sharma P;Allison JP;Chin L;Wargo JA
通讯作者：
Wargo JA
影响因子：
3.7
作者：
Hoshida Y;Brunet JP;Tamayo P;Golub TR;Mesirov JP
通讯作者：
Mesirov JP
影响因子：
64.5
作者：
Liu J;Lichtenberg T;Hoadley KA;Poisson LM;Lazar AJ;Cherniack AD;Kovatich AJ;Benz CC;Levine DA;Lee AV;Omberg L;Wolf DM;Shriver CD;Thorsson V;Cancer Genome Atlas Research Network;Hu H
通讯作者：
Hu H
影响因子：
45.3
作者：
Ballman, Karla V.
通讯作者：
Ballman, Karla V.