Comprehensive Multiomic Resource for HPV-Negative Head and Neck Cancers

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In a comprehensive molecular characterization of the most common type of head and neck cancer, researchers from the United States and Poland have clarified the contribution of key cancer-associated genes, proteins, and signaling pathways in these cancers, while proposing possible new treatment avenues. Their investigation of human papillomavirus (HPV)-negative head and neck squamous cell carcinomas was published by Huang et al in Cancer Cell.

The study involved tumors from 108 patients who had not yet received cancer treatment, as well as 66 samples of healthy tissue surrounding the tumors. The study systematically catalogued HPV-negative head and neck squamous cell carcinoma–associated proteins, phosphosites, and signaling pathways, finding three distinct subtypes of head and neck squamous cell carcinoma.

Researchers used genomic and proteomic technologies to determine head and neck squamous cell carcinoma proteogenomic characteristics, defined as genomics, epigenomics, transcriptomics, proteomics, and phosphoproteomics.

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The first subtype of head and neck squamous cell carcinoma identified by researchers, dubbed CIN, showed the worst prognosis. It was associated with the larynx, a strong history of smoking, and high instability of chromosomes. Since this subtype was associated with frequent aberrations of the CCND1 and CDKN2A genes, and high activity of the enzymes CDK4 and CDK6, this type of cancer may respond best to treatment with CDK4/6 inhibitors.

The second subtype, dubbed basal, showed protein elevations of several basal factors, the most basic set of proteins needed to activate gene transcription. It was characterized by high activity in the EGFR signaling pathway and high expression of molecules called AREG and TNFA, which attach to the EGFR tumor protein. Therefore, researchers say, these cancers may respond best to treatment with monoclonal antibodies that are aimed at EGFR.

The third subtype, called immune, was found among tumors in patients who did not smoke and showed high expression of multiple immune checkpoint proteins. Researchers say these tumors may best respond to immune checkpoint inhibitors.

Overall, 32% of CIN tumors, 62% of basal tumors, and 83% of immune tumors had high potential for the suggested treatments.

Researchers also found two modes of activation of EGFR, suggesting a new strategy to stratify head and neck squamous cell carcinomas based on the number of molecules bound to EGFR, for effective treatment with monoclonal antibodies that enlist the natural immune system to fight cancer. Additionally, they noted that widespread deletion of immune modulatory genes among these cancers accounts for a loss of ability to produce an immune response.

“This study extends our biological understanding of HPV-negative head and neck squamous cell carcinomas and generates therapeutic hypotheses that may serve as the basis for future studies and clinical trials toward molecularly guided precision medicine treatment of this aggressive cancer type,” said principal investigator Daniel Chan, PhD, Professor of Pathology and Oncology and Director of the Center for Biomarker Discovery and Translation at the Johns Hopkins University School of Medicine.

The three subtypes and suggested treatments “are quite major findings,” said Hui Zhang, PhD, co-principal investigator of the study, Professor of Pathology and Oncology, and Director of the Mass Spectrometry Core facility at the Johns Hopkins University School of Medicine. “Previously, patients would be treated using different options, but there was no systematic way to know which treatment would be the best option for certain patients.”

The team has begun similar work to investigate properties of HPV-positive head and neck squamous cell carcinomas.

Disclosure: The work was supported by the National Cancer Institute Clinical Proteomic Tumor Analysis Consortium, a Cancer Prevention Institute of Texas award, the Translational Breast Cancer Research Training Program, and the McNair Foundation. For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.