Proteogenomic insights into the biology and treatment of HPV-negative head and neck squamous cell carcinoma,Cancer Cell

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Proteogenomic insights into the biology and treatment of HPV-negative head and neck squamous cell carcinoma
Cancer Cell ( IF 48.8 ) Pub Date : 2021-01-07 , DOI: 10.1016/j.ccell.2020.12.007
Chen Huang ₁ , Lijun Chen ₂ , Sara R Savage ₁ , Rodrigo Vargas Eguez ₂ , Yongchao Dou ₁ , Yize Li ₃ , Felipe da Veiga Leprevost ₄ , Eric J Jaehnig ₁ , Jonathan T Lei ₁ , Bo Wen ₁ , Michael Schnaubelt ₂ , Karsten Krug ₅ , Xiaoyu Song ₆ , Marcin Cieślik ₇ , Hui-Yin Chang ₄ , Matthew A Wyczalkowski ₃ , Kai Li ₁ , Antonio Colaprico ₈ , Qing Kay Li ₂ , David J Clark ₂ , Yingwei Hu ₂ , Liwei Cao ₂ , Jianbo Pan ₉ , Yuefan Wang ₂ , Kyung-Cho Cho ₂ , Zhiao Shi ₁ , Yuxing Liao ₁ , Wen Jiang ₁ , Meenakshi Anurag ₁₀ , Jiayi Ji ₆ , Seungyeul Yoo ₁₁ , Daniel Cui Zhou ₃ , Wen-Wei Liang ₃ , Michael Wendl ₃ , Pankaj Vats ₁₂ , Steven A Carr ₅ , D R Mani ₅ , Zhen Zhang ₂ , Jiang Qian ₁₃ , Xi S Chen ₈ , Alexander R Pico ₁₄ , Pei Wang ₁₁ , Arul M Chinnaiyan ₇ , Karen A Ketchum ₁₅ , Christopher R Kinsinger ₁₆ , Ana I Robles ₁₆ , Eunkyung An ₁₆ , Tara Hiltke ₁₆ , Mehdi Mesri ₁₆ , Mathangi Thiagarajan ₁₇ , Alissa M Weaver ₁₈ , Andrew G Sikora ₁₉ , Jan Lubiński ₂₀ , Małgorzata Wierzbicka ₂₁ , Maciej Wiznerowicz ₂₂ , Shankha Satpathy ₅ , Michael A Gillette ₂₃ , George Miles ₁ , Matthew J Ellis ₁₀ , Gilbert S Omenn ₂₄ , Henry Rodriguez ₁₆ , Emily S Boja ₁₆ , Saravana M Dhanasekaran ₂₅ , Li Ding ₃ , Alexey I Nesvizhskii ₇ , Adel K El-Naggar ₂₆ , Daniel W Chan ₂ , Hui Zhang ₂ , Bing Zhang ₁ ,

Affiliation

Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Department of Pathology and Oncology, Johns Hopkins University, Baltimore, MD 21231, USA.
Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA.
Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Division of Biostatistics, Department of Public Health Science, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Department of Pathology and Oncology, Johns Hopkins University, Baltimore, MD 21231, USA; Department of Ophthalmology, Johns Hopkins University, Baltimore, MD 21231, USA.
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.
Department of Genetics and Genomic Sciences and Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
Department of Ophthalmology, Johns Hopkins University, Baltimore, MD 21231, USA.
Institute of Data Science and Biotechnology, Gladstone Institutes, San Francisco, CA 94158, USA.
ESAC, Inc., Rockville, MD 20850, United States.
Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, MD 20892, USA.
Leidos Biomedical Research Inc., Frederick NaVonal Laboratory for Cancer Research, Frederick, MD 21702, USA.
Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Department of Head and Neck Surgery, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, 71-252 Szczecin, Poland; International Institute for Molecular Oncology, 60-203 Poznań, Poland.
Poznań University of Medical Sciences, 61-701 Poznań, Poland; Institute of Human Genetics Polish Academy of Sciences, 60-479 Poznań, Poland.
International Institute for Molecular Oncology, 60-203 Poznań, Poland; Poznań University of Medical Sciences, 61-701 Poznań, Poland.
Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
Department of Pathology, Division of Pathology and Laboratory Medicine, MD Anderson Cancer Center, Houston, TX 77030, USA.

We present a proteogenomic study of 108 human papilloma virus (HPV)-negative head and neck squamous cell carcinomas (HNSCCs). Proteomic analysis systematically catalogs HNSCC-associated proteins and phosphosites, prioritizes copy number drivers, and highlights an oncogenic role for RNA processing genes. Proteomic investigation of mutual exclusivity between FAT1 truncating mutations and 11q13.3 amplifications reveals dysregulated actin dynamics as a common functional consequence. Phosphoproteomics characterizes two modes of EGFR activation, suggesting a new strategy to stratify HNSCCs based on EGFR ligand abundance for effective treatment with inhibitory EGFR monoclonal antibodies. Widespread deletion of immune modulatory genes accounts for low immune infiltration in immune-cold tumors, whereas concordant upregulation of multiple immune checkpoint proteins may underlie resistance to anti-programmed cell death protein 1 monotherapy in immune-hot tumors. Multi-omic analysis identifies three molecular subtypes with high potential for treatment with CDK inhibitors, anti-EGFR antibody therapy, and immunotherapy, respectively. Altogether, proteogenomics provides a systematic framework to inform HNSCC biology and treatment.

中文翻译：

蛋白质组学对 HPV 阴性头颈部鳞状细胞癌生物学和治疗的见解

我们对 108 例人乳头瘤病毒 (HPV) 阴性的头颈部鳞状细胞癌 (HNSCC) 进行了蛋白质组学研究。蛋白质组学分析系统地对 HNSCC 相关蛋白和磷酸位点进行分类，优先考虑拷贝数驱动因素，并突出 RNA 加工基因的致癌作用。FAT1互斥性的蛋白质组学研究截断突变和 11q13.3 扩增揭示了肌动蛋白动力学失调是一种常见的功能后果。磷酸蛋白质组学表征了 EGFR 激活的两种模式，提出了一种基于 EGFR 配体丰度对 HNSCC 进行分层的新策略，以有效治疗抑制性 EGFR 单克隆抗体。免疫调节基因的广泛缺失是免疫冷肿瘤免疫浸润低的原因，而多个免疫检查点蛋白的一致上调可能是免疫热肿瘤对抗程序性细胞死亡蛋白 1 单一疗法耐药的基础。多组学分析确定了三种具有高潜力的分子亚型，分别用于 CDK 抑制剂、抗 EGFR 抗体治疗和免疫治疗。共，

更新日期：2021-03-08

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