Journal
NATURE COMMUNICATIONS
Volume 11, Issue 1, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-020-14730-1
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Funding
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health
- National Cancer Institute, National Institutes of Health [HHSN261200800001E]
- Institut National du Cancer (INCa), France [SHSESP 16-006]
- National Cancer Institute [CA78527]
- Einstein Cancer Research Center from the National Cancer Institute [P30CA013330]
- Gerstner Scholars Fellowship from the Gerstner Family Foundation at the American Museum of Natural History
- NATIONAL CANCER INSTITUTE [ZIACP010228] Funding Source: NIH RePORTER
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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 APOBEC3induced 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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