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APOBEC Mutagenesis Is Concordant between Tumor and Viral Genomes in HPV-Positive Head and Neck Squamous Cell Carcinoma

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 a...

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Autores principales: Faden, Daniel L., Kuhs, Krystle A. Lang, Lin, Maoxuan, Langenbucher, Adam, Pinheiro, Maisa, Yeager, Meredith, Cullen, Michael, Boland, Joseph F., Steinberg, Mia, Bass, Sara, Lewis, James S., Lawrence, Michael S., Ferris, Robert L., Mirabello, Lisa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8402723/
https://www.ncbi.nlm.nih.gov/pubmed/34452530
http://dx.doi.org/10.3390/v13081666
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author Faden, Daniel L.
Kuhs, Krystle A. Lang
Lin, Maoxuan
Langenbucher, Adam
Pinheiro, Maisa
Yeager, Meredith
Cullen, Michael
Boland, Joseph F.
Steinberg, Mia
Bass, Sara
Lewis, James S.
Lawrence, Michael S.
Ferris, Robert L.
Mirabello, Lisa
author_facet Faden, Daniel L.
Kuhs, Krystle A. Lang
Lin, Maoxuan
Langenbucher, Adam
Pinheiro, Maisa
Yeager, Meredith
Cullen, Michael
Boland, Joseph F.
Steinberg, Mia
Bass, Sara
Lewis, James S.
Lawrence, Michael S.
Ferris, Robert L.
Mirabello, Lisa
author_sort Faden, Daniel L.
collection PubMed
description 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.
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spelling pubmed-84027232021-08-29 APOBEC Mutagenesis Is Concordant between Tumor and Viral Genomes in HPV-Positive Head and Neck Squamous Cell Carcinoma Faden, Daniel L. Kuhs, Krystle A. Lang Lin, Maoxuan Langenbucher, Adam Pinheiro, Maisa Yeager, Meredith Cullen, Michael Boland, Joseph F. Steinberg, Mia Bass, Sara Lewis, James S. Lawrence, Michael S. Ferris, Robert L. Mirabello, Lisa Viruses Article 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. MDPI 2021-08-23 /pmc/articles/PMC8402723/ /pubmed/34452530 http://dx.doi.org/10.3390/v13081666 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Faden, Daniel L.
Kuhs, Krystle A. Lang
Lin, Maoxuan
Langenbucher, Adam
Pinheiro, Maisa
Yeager, Meredith
Cullen, Michael
Boland, Joseph F.
Steinberg, Mia
Bass, Sara
Lewis, James S.
Lawrence, Michael S.
Ferris, Robert L.
Mirabello, Lisa
APOBEC Mutagenesis Is Concordant between Tumor and Viral Genomes in HPV-Positive Head and Neck Squamous Cell Carcinoma
title APOBEC Mutagenesis Is Concordant between Tumor and Viral Genomes in HPV-Positive Head and Neck Squamous Cell Carcinoma
title_full APOBEC Mutagenesis Is Concordant between Tumor and Viral Genomes in HPV-Positive Head and Neck Squamous Cell Carcinoma
title_fullStr APOBEC Mutagenesis Is Concordant between Tumor and Viral Genomes in HPV-Positive Head and Neck Squamous Cell Carcinoma
title_full_unstemmed APOBEC Mutagenesis Is Concordant between Tumor and Viral Genomes in HPV-Positive Head and Neck Squamous Cell Carcinoma
title_short APOBEC Mutagenesis Is Concordant between Tumor and Viral Genomes in HPV-Positive Head and Neck Squamous Cell Carcinoma
title_sort apobec mutagenesis is concordant between tumor and viral genomes in hpv-positive head and neck squamous cell carcinoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8402723/
https://www.ncbi.nlm.nih.gov/pubmed/34452530
http://dx.doi.org/10.3390/v13081666
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