Apobec mutagenesis is concordant between tumor and viral genomes in hpv-positive head and neck squamous cell carcinoma

Daniel L. Faden, Krystle A. Lang Kuhs, Maoxuan Lin, Adam Langenbucher, Maisa Pinheiro, Meredith Yeager, Michael Cullen, Joseph F. Boland, Mia Steinberg, Sara Bass, James S. Lewis, Michael S. Lawrence, Robert L. Ferris, Lisa Mirabello

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

APOBEC is a mutagenic source in human papillomavirus (HPV)-mediated malignancies, including HPV+ oropharyngeal squamous cell carcinoma (HPV + OPSCC), and in HPV genomes. It is unknown why APOBEC mutations predominate in HPV + OPSCC, or if the APOBEC-induced mutations observed in both human cancers and HPV genomes are directly linked. We performed sequencing of host somatic exomes, transcriptomes, and HPV16 genomes from 79 HPV + OPSCC samples, quantifying APOBEC mutational burden and activity in both host and virus. APOBEC was the dominant mutational signature in somatic exomes. In viral genomes, there was a mean of five (range 0–29) mutations per genome. The mean of APOBEC mutations in viral genomes was one (range 0–5). Viral APOBEC mutations, compared to non-APOBEC mutations, were more likely to be low-variant allele fraction mutations, suggesting that APOBEC mutagenesis actively occurrs in viral genomes during infection. HPV16 APOBEC-induced mutation patterns in OPSCC were similar to those previously observed in cervical samples. Paired host and viral analyses revealed that APOBEC-enriched tumor samples had higher viral APOBEC mutation rates (p = 0.028), and APOBEC-associated RNA editing (p = 0.008), supporting the concept that APOBEC mutagenesis in host and viral genomes is directly linked and occurrs during infection. Using paired sequencing of host somatic exomes, transcriptomes, and viral genomes, we demonstrated for the first-time definitive evidence of concordance between tumor and viral APOBEC mutagenesis. This finding provides a missing link connecting APOBEC mutagenesis in host and virus and supports a common mechanism driving APOBEC dysregulation.

Original languageEnglish
Article number1666
JournalViruses
Volume13
Issue number8
DOIs
StatePublished - Aug 2021

Bibliographical note

Funding Information:
Funding: This research was funded by DLF (sundry).

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • APOBEC
  • HPV
  • Humanpapilloma virus
  • Oropharyngeal cancer
  • Oropharyngeal squamoucell carcinoma

ASJC Scopus subject areas

  • Infectious Diseases
  • Virology

Fingerprint

Dive into the research topics of 'Apobec mutagenesis is concordant between tumor and viral genomes in hpv-positive head and neck squamous cell carcinoma'. Together they form a unique fingerprint.

Cite this