Mutations in the HPV16 genome induced by APOBEC3 are associated with viral clearance

Bin Zhu; Yanzi Xiao; Meredith Yeager; Gary Clifford; Nicolas Wentzensen; Michael Cullen; Joseph F. Boland; Sara Bass; Mia K. Steinberg; Tina Raine-Bennett; Dong Hyuk Lee; Robert D. Burk; Maisa Pinheiro; Lei Song; Michael Dean; Chase W. Nelson; Laurie Burdett; Kai Yu; David Roberson; Thomas Lorey; Silvia Franceschi; Philip E. Castle; Joan Walker; Rosemary Zuna; Mark Schiffman; Lisa Mirabello

doi:10.1038/s41467-020-14730-1

Mutations in the HPV16 genome induced by APOBEC3 are associated with viral clearance

Bin Zhu, Yanzi Xiao, Meredith Yeager, Gary Clifford, Nicolas Wentzensen, Michael Cullen, Joseph F. Boland, Sara Bass, Mia K. Steinberg, Tina Raine-Bennett, Dong Hyuk Lee, Robert D. Burk, Maisa Pinheiro, Lei Song, Michael Dean, Chase W. Nelson, Laurie Burdett, Kai Yu, David Roberson, Thomas LoreySilvia Franceschi, Philip E. Castle, Joan Walker, Rosemary Zuna, Mark Schiffman, Lisa Mirabello

Pediatrics

Research output: Contribution to journal › Article › peer-review

49 Scopus citations

Abstract

HPV16 causes half of cervical cancers worldwide; for unknown reasons, most infections resolve within two years. Here, we analyze the viral genomes of 5,328 HPV16-positive case-control samples to investigate mutational signatures and the role of human APOBEC3-induced mutations in viral clearance and cervical carcinogenesis. We identify four de novo mutational signatures, one of which matches the COSMIC APOBEC-associated signature 2. The viral genomes of the precancer/cancer cases are less likely to contain within-host somatic HPV16 APOBEC3-induced mutations (Fisher’s exact test, P = 6.2 x 10⁻¹⁴), and have a 30% lower nonsynonymous APOBEC3 mutation burden compared to controls. We replicate the low prevalence of HPV16 APOBEC3-induced mutations in 1,749 additional cases. APOBEC3 mutations also historically contribute to the evolution of HPV16 lineages. We demonstrate that cervical infections with a greater burden of somatic HPV16 APOBEC3-induced mutations are more likely to be benign or subsequently clear, suggesting they may reduce persistence, and thus progression, within the host.

Original language	English (US)
Article number	886
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-14730-1
State	Published - Dec 1 2020

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-020-14730-1

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Zhu, B., Xiao, Y., Yeager, M., Clifford, G., Wentzensen, N., Cullen, M., Boland, J. F., Bass, S., Steinberg, M. K., Raine-Bennett, T., Lee, D. H., Burk, R. D., Pinheiro, M., Song, L., Dean, M., Nelson, C. W., Burdett, L., Yu, K., Roberson, D., ... Mirabello, L. (2020). Mutations in the HPV16 genome induced by APOBEC3 are associated with viral clearance. Nature communications, 11(1), Article 886. https://doi.org/10.1038/s41467-020-14730-1

Zhu, B, Xiao, Y, Yeager, M, Clifford, G, Wentzensen, N, Cullen, M, Boland, JF, Bass, S, Steinberg, MK, Raine-Bennett, T, Lee, DH, Burk, RD, Pinheiro, M, Song, L, Dean, M, Nelson, CW, Burdett, L, Yu, K, Roberson, D, Lorey, T, Franceschi, S, Castle, PE, Walker, J, Zuna, R, Schiffman, M & Mirabello, L 2020, 'Mutations in the HPV16 genome induced by APOBEC3 are associated with viral clearance', Nature communications, vol. 11, no. 1, 886. https://doi.org/10.1038/s41467-020-14730-1

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title = "Mutations in the HPV16 genome induced by APOBEC3 are associated with viral clearance",

abstract = "HPV16 causes half of cervical cancers worldwide; for unknown reasons, most infections resolve within two years. Here, we analyze the viral genomes of 5,328 HPV16-positive case-control samples to investigate mutational signatures and the role of human APOBEC3-induced mutations in viral clearance and cervical carcinogenesis. We identify four de novo mutational signatures, one of which matches the COSMIC APOBEC-associated signature 2. The viral genomes of the precancer/cancer cases are less likely to contain within-host somatic HPV16 APOBEC3-induced mutations (Fisher{\textquoteright}s exact test, P = 6.2 x 10−14), and have a 30% lower nonsynonymous APOBEC3 mutation burden compared to controls. We replicate the low prevalence of HPV16 APOBEC3-induced mutations in 1,749 additional cases. APOBEC3 mutations also historically contribute to the evolution of HPV16 lineages. We demonstrate that cervical infections with a greater burden of somatic HPV16 APOBEC3-induced mutations are more likely to be benign or subsequently clear, suggesting they may reduce persistence, and thus progression, within the host.",

author = "Bin Zhu and Yanzi Xiao and Meredith Yeager and Gary Clifford and Nicolas Wentzensen and Michael Cullen and Boland, {Joseph F.} and Sara Bass and Steinberg, {Mia K.} and Tina Raine-Bennett and Lee, {Dong Hyuk} and Burk, {Robert D.} and Maisa Pinheiro and Lei Song and Michael Dean and Nelson, {Chase W.} and Laurie Burdett and Kai Yu and David Roberson and Thomas Lorey and Silvia Franceschi and Castle, {Philip E.} and Joan Walker and Rosemary Zuna and Mark Schiffman and Lisa Mirabello",

note = "Funding Information: This study was funded by the intramural research program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does neither necessarily reflect the views or policies of the Department of Health and Human Services nor mention trade names, commercial products, or organizations imply endorsement by the U.S. Government. Work at IARC was supported by a grant from the Institut National du Cancer (INCa), France (SHSESP 16-006). Work by R.D.B. was supported in part by the National Cancer Institute (CA78527) and the Einstein Cancer Research Center (P30CA013330) from the National Cancer Institute (to R.D.B.). C.W.N. was supported by a Gerstner Scholars Fellowship from the Gerstner Family Foundation at the American Museum of Natural History. Publisher Copyright: {\textcopyright} 2020, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.",

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AU - Zhu, Bin

AU - Xiao, Yanzi

AU - Yeager, Meredith

AU - Clifford, Gary

AU - Wentzensen, Nicolas

AU - Cullen, Michael

AU - Boland, Joseph F.

AU - Bass, Sara

AU - Steinberg, Mia K.

AU - Raine-Bennett, Tina

AU - Lee, Dong Hyuk

AU - Burk, Robert D.

AU - Pinheiro, Maisa

AU - Song, Lei

AU - Dean, Michael

AU - Nelson, Chase W.

AU - Burdett, Laurie

AU - Yu, Kai

AU - Roberson, David

AU - Lorey, Thomas

AU - Franceschi, Silvia

AU - Castle, Philip E.

AU - Walker, Joan

AU - Zuna, Rosemary

AU - Schiffman, Mark

AU - Mirabello, Lisa

N1 - Funding Information: This study was funded by the intramural research program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does neither necessarily reflect the views or policies of the Department of Health and Human Services nor mention trade names, commercial products, or organizations imply endorsement by the U.S. Government. Work at IARC was supported by a grant from the Institut National du Cancer (INCa), France (SHSESP 16-006). Work by R.D.B. was supported in part by the National Cancer Institute (CA78527) and the Einstein Cancer Research Center (P30CA013330) from the National Cancer Institute (to R.D.B.). C.W.N. was supported by a Gerstner Scholars Fellowship from the Gerstner Family Foundation at the American Museum of Natural History. Publisher Copyright: © 2020, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

PY - 2020/12/1

Y1 - 2020/12/1

N2 - HPV16 causes half of cervical cancers worldwide; for unknown reasons, most infections resolve within two years. Here, we analyze the viral genomes of 5,328 HPV16-positive case-control samples to investigate mutational signatures and the role of human APOBEC3-induced mutations in viral clearance and cervical carcinogenesis. We identify four de novo mutational signatures, one of which matches the COSMIC APOBEC-associated signature 2. The viral genomes of the precancer/cancer cases are less likely to contain within-host somatic HPV16 APOBEC3-induced mutations (Fisher’s exact test, P = 6.2 x 10−14), and have a 30% lower nonsynonymous APOBEC3 mutation burden compared to controls. We replicate the low prevalence of HPV16 APOBEC3-induced mutations in 1,749 additional cases. APOBEC3 mutations also historically contribute to the evolution of HPV16 lineages. We demonstrate that cervical infections with a greater burden of somatic HPV16 APOBEC3-induced mutations are more likely to be benign or subsequently clear, suggesting they may reduce persistence, and thus progression, within the host.

AB - HPV16 causes half of cervical cancers worldwide; for unknown reasons, most infections resolve within two years. Here, we analyze the viral genomes of 5,328 HPV16-positive case-control samples to investigate mutational signatures and the role of human APOBEC3-induced mutations in viral clearance and cervical carcinogenesis. We identify four de novo mutational signatures, one of which matches the COSMIC APOBEC-associated signature 2. The viral genomes of the precancer/cancer cases are less likely to contain within-host somatic HPV16 APOBEC3-induced mutations (Fisher’s exact test, P = 6.2 x 10−14), and have a 30% lower nonsynonymous APOBEC3 mutation burden compared to controls. We replicate the low prevalence of HPV16 APOBEC3-induced mutations in 1,749 additional cases. APOBEC3 mutations also historically contribute to the evolution of HPV16 lineages. We demonstrate that cervical infections with a greater burden of somatic HPV16 APOBEC3-induced mutations are more likely to be benign or subsequently clear, suggesting they may reduce persistence, and thus progression, within the host.

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Mutations in the HPV16 genome induced by APOBEC3 are associated with viral clearance

Abstract

ASJC Scopus subject areas

UN SDGs

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