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.
Recommended citation: Huang C, Chen L, Savage SR, Eguez RV, Dou Y, Li Y, da Veiga Leprevost F, Jaehnig EJ, Lei JT, Wen B, Schnaubelt M, Krug K, Song X, Cieślik M, Chang HY, Wyczalkowski MA, Li K, Colaprico A, Li QK, Clark DJ, Hu Y, Cao L, Pan J, Wang Y, Cho KC, Shi Z, Liao Y, Jiang W, Anurag M, Ji J, Yoo S, Zhou DC, Liang WW, Wendl M, Vats P, Carr SA, Mani DR, Zhang Z, Qian J, Chen XS, Pico AR, Wang P, Chinnaiyan AM, Ketchum KA, Kinsinger CR, Robles AI, An E, Hiltke T, Mesri M, Thiagarajan M, Weaver AM, Sikora AG, Lubiński J, Wierzbicka M, Wiznerowicz M, Satpathy S, Gillette MA, Miles G, Ellis MJ, Omenn GS, Rodriguez H, Boja ES, Dhanasekaran SM, Ding L, Nesvizhskii AI, El-Naggar AK, Chan DW, Zhang H, Zhang B; Clinical Proteomic Tumor Analysis Consortium. Proteogenomic insights into the biology and treatment of HPV-negative head and neck squamous cell carcinoma. Cancer Cell. 2021 Jan 5:S1535-6108(20)30655-3. doi: 10.1016/j.ccell.2020.12.007. Epub ahead of print. PMID: 33417831.