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

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.

Citation

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, Lisa Mirabello. Mutations in the HPV16 genome induced by APOBEC3 are associated with viral clearance. Nature communications. 2020 Feb 14;11(1):886

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PMID: 32060290

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