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, DongHyuk 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 and Lisa Mirabello ()
Additional contact information
Bin Zhu: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health
Yanzi Xiao: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health
Meredith Yeager: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health
Gary Clifford: Infections and Cancer Epidemiology Group, International Agency for Research on Cancer
Nicolas Wentzensen: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health
Michael Cullen: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health
Joseph F. Boland: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health
Sara Bass: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health
Mia K. Steinberg: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health
Tina Raine-Bennett: Women’s Health Research Institute, Division of Research, Kaiser Permanente Northern California
DongHyuk Lee: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health
Robert D. Burk: Departments of Pediatrics, Microbiology and Immunology, and Obstetrics & Gynecology and Women’s Health, Albert Einstein College of Medicine
Maisa Pinheiro: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health
Lei Song: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health
Michael Dean: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health
Chase W. Nelson: Sackler Institute for Comparative Genomics, American Museum of Natural History
Laurie Burdett: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health
Kai Yu: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health
David Roberson: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health
Thomas Lorey: Regional Laboratory, Kaiser Permanente Northern California
Silvia Franceschi: CRO Aviano National Cancer Institute IRCCS
Philip E. Castle: Department of Epidemiology and Population Health, Albert Einstein College of Medicine
Joan Walker: University of Oklahoma Health Sciences Center
Rosemary Zuna: University of Oklahoma Health Sciences Center
Mark Schiffman: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health
Lisa Mirabello: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-14730-1

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