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Title	Proteogenomic insights into the biology and treatment of HPV-negative head and neck squamous cell carcinoma.
Author	Huang, Chen; Chen, Lijun; Savage, Sara R; Eguez, Rodrigo Vargas; Dou, Yongchao; Li, Yize; da Veiga Leprevost, Felipe; Jaehnig, Eric J; Lei, Jonathan T; Wen, Bo; Schnaubelt, Michael; Krug, Karsten; Song, Xiaoyu; Cieslik, Marcin; Chang, Hui-Yin; Wyczalkowski, Matthew A; Li, Kai; Colaprico, Antonio; Li, Qing Kay; Clark, David J; Hu, Yingwei; Cao, Liwei; Pan, Jianbo; Wang, Yuefan; Cho, Kyung-Cho; Shi, Zhiao; Liao, Yuxing; Jiang, Wen; Anurag, Meenakshi; Ji, Jiayi; Yoo, Seungyeul; Zhou, Daniel Cui; Liang, Wen-Wei; Wendl, Michael; Vats, Pankaj; Carr, Steven A; Mani, D R; Zhang, Zhen; Qian, Jiang; Chen, Xi S; Pico, Alexander R; Wang, Pei; Chinnaiyan, Arul M; Ketchum, Karen A; Kinsinger, Christopher R; Robles, Ana I; An, Eunkyung; Hiltke, Tara; Mesri, Mehdi; Thiagarajan, Mathangi; Weaver, Alissa M; Sikora, Andrew G; Lubinski, Jan; Wierzbicka, Malgorzata; Wiznerowicz, Maciej; Satpathy, Shankha; Gillette, Michael A; Miles, George; Ellis, Matthew J; Omenn, Gilbert S; Rodriguez, Henry; Boja, Emily S; Dhanasekaran, Saravana M; Ding, Li; Nesvizhskii, Alexey I; El-Naggar, Adel K; Chan, Daniel W; Zhang, Hui; Zhang, Bing
Journal	Cancer Cell	Publication Year/Month	2021-Mar
PMID	33417831	PMCID	PMC7946781
Affiliation + expend	1.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.
	2.Department of Pathology and Oncology, Johns Hopkins University, Baltimore, MD 21231, USA.
	3.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.
	4.Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
	5.Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
	6.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.
	7.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.
	8.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.
	9.Department of Pathology and Oncology, Johns Hopkins University, Baltimore, MD 21231, USA; Department of Ophthalmology, Johns Hopkins University, Baltimore, MD 21231, USA.
	10.Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.
	11.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.
	12.Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
	13.Department of Ophthalmology, Johns Hopkins University, Baltimore, MD 21231, USA.
	14.Institute of Data Science and Biotechnology, Gladstone Institutes, San Francisco, CA 94158, USA.
	15.ESAC, Inc., Rockville, MD 20850, United States.
	16.Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, MD 20892, USA.
	17.Leidos Biomedical Research Inc., Frederick NaVonal Laboratory for Cancer Research, Frederick, MD 21702, USA.
	18.Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
	19.Department of Head and Neck Surgery, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
	20.Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, 71-252 Szczecin, Poland; International Institute for Molecular Oncology, 60-203 Poznan, Poland.
	21.Poznan University of Medical Sciences, 61-701 Poznan, Poland; Institute of Human Genetics Polish Academy of Sciences, 60-479 Poznan, Poland.
	22.International Institute for Molecular Oncology, 60-203 Poznan, Poland; Poznan University of Medical Sciences, 61-701 Poznan, Poland.
	23.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.
	24.Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
	25.Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
	26.Department of Pathology, Division of Pathology and Laboratory Medicine, MD Anderson Cancer Center, Houston, TX 77030, USA.
	27.Department of Pathology and Oncology, Johns Hopkins University, Baltimore, MD 21231, USA. Electronic address: dchan@jhmi.edu.
	28.Department of Pathology and Oncology, Johns Hopkins University, Baltimore, MD 21231, USA. Electronic address: huizhang@jhu.edu.
	29.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. Electronic address: bing.zhang@bcm.edu.

Abstract

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.

Keywords

CDK inhibitor

CPTAC

EGFR mAb

HNSCC

combination immune checkpoint blockade

immune evasion

immunotherapy

predictive biomarker

proteogenomics

proteomics

MeSH terms