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PubMed · 40925715

Circulating tumor human papillomavirus DNA whole genome sequencing enables human papillomavirus-associated oropharynx cancer early detection.

Dipon Das·Shun Hirayama·Ling Aye·Michael E Bryan·Saskia Naegele·Brian Zhao·Vasileios Efthymiou·Julia Mendel·Adam S Fisch·Zoe Guan·Lea Kröller·Birgitta E Michels·Tim Waterboer·Jeremy D Richmon·Viktor Adalsteinsson·Michael S Lawrence·Matthew G Crowson·A John Iafrate·Daniel L Faden
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Abstract

BACKGROUND: Early detection of HPV-associated oropharyngeal squamous cell carcinoma, the most common HPV cancer in the United States, could reduce disease-related morbidity and mortality, yet currently, there are no early detection tests. HPV circulating tumor DNA (ctDNA) is a sensitive and specific biomarker for HPV-associated oropharyngeal squamous cell carcinoma at diagnosis. It is unknown if ctDNA HPV is detectable prior to diagnosis, and thus its potential as an early detection test is also unknown. METHODS: Plasma samples from the Mass General Brigham Biobank collected 1.3-10.8 years prior to diagnosis from HPV-associated oropharyngeal squamous cell carcinoma patients (n = 28) and age- and sex-matched controls (n = 28) were blinded and run on a newly developed and validated multifeature HPV whole genome sequencing liquid biopsy assay and a validated HPV antibody assay. RESULTS: HPV ctDNA results were positive in 22 of 28 prediagnostic samples from HPV-associated oropharyngeal squamous cell carcinoma cases (sensitivity 79%) with a maximum lead time of 7.8 years. HPV ctDNA results were negative in all controls (0 of 28, 100% specificity). Diagnostic accuracy was highest within 4 years of cancer diagnosis and was higher than HPV Ab detection within the same timeframe (P = .004). Application of a machine-learning model trained and tested on an independent cohort of 306 cases and controls increased the sensitivity of detection to 27 of 28 cases (overall sensitivity 96%) and the maximum lead time to 10.3 years. CONCLUSIONS: HPV ctDNA can be detected in the blood years prior to diagnosis with HPV-associated oropharyngeal squamous cell carcinoma, with high specificity, in a case-control cohort of 56 participants. HPV ctDNA detection alone, or in combination with previously identified serological biomarkers, may be a feasible approach to early detection of HPV-associated oropharyngeal squamous cell carcinoma.

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HumansOropharyngeal NeoplasmsEarly Detection of CancerMaleFemalePapillomavirus InfectionsCirculating Tumor DNAMiddle AgedWhole Genome SequencingAgedDNA, ViralBiomarkers, TumorPapillomaviridaeCase-Control StudiesCarcinoma, Squamous CellSensitivity and SpecificitySquamous Cell Carcinoma of Head and NeckAdultHuman Papillomavirus VirusesJournal Article

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Dipon Das, Shun Hirayama, Ling Aye, Michael E Bryan, Saskia Naegele, Brian Zhao, Vasileios Efthymiou, Julia Mendel, Adam S Fisch, Zoe Guan, Lea Kröller, Birgitta E Michels, Tim Waterboer, Jeremy D Richmon, Viktor Adalsteinsson, Michael S Lawrence, Matthew G Crowson, A John Iafrate, Daniel L Faden. 2026-01-01. Circulating tumor human papillomavirus DNA whole genome sequencing enables human papillomavirus-associated oropharynx cancer early detection.. https://doi.org/10.1093/jnci%2Fdjaf249

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