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

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Mutations in the HPV16 genome induced by APOBEC3 are associated with viral clearance.
Nature Communications ( IF 14.7 ) Pub Date : 2020-02-14 , DOI: 10.1038/s41467-020-14730-1
Bin Zhu ₁ , Yanzi Xiao ₁ , Meredith Yeager _{1,

2} , Gary Clifford ₃ , Nicolas Wentzensen ₁ , Michael Cullen _{1,

2} , Joseph F Boland _{1,

2} , Sara Bass _{1,

2} , Mia K Steinberg _{1,

2} , Tina Raine-Bennett ₄ , DongHyuk Lee ₁ , Robert D Burk _{5,

6} , Maisa Pinheiro ₁ , Lei Song _{1,

2} , Michael Dean ₁ , Chase W Nelson ₇ , Laurie Burdett _{1,

2} , Kai Yu ₁ , David Roberson _{1,

2} , Thomas Lorey ₈ , Silvia Franceschi ₉ , Philip E Castle ₆ , Joan Walker ₁₀ , Rosemary Zuna ₁₀ , Mark Schiffman ₁ , Lisa Mirabello ₁

Affiliation

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA.
Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
Infections and Cancer Epidemiology Group, International Agency for Research on Cancer, 150 Cours Albert Thomas, 69372, Lyon, Cedex 08, France.
Women's Health Research Institute, Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.
Departments of Pediatrics, Microbiology and Immunology, and Obstetrics & Gynecology and Women's Health, Albert Einstein College of Medicine, Bronx, NY, USA.
Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
Sackler Institute for Comparative Genomics, American Museum of Natural History, New York, NY, USA.
Regional Laboratory, Kaiser Permanente Northern California, Oakland, CA, USA.
CRO Aviano National Cancer Institute IRCCS, Aviano, Italy.
University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.

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.

中文翻译：

APOBEC3 诱导的 HPV16 基因组突变与病毒清除相关。

全球一半的宫颈癌是由 HPV16 引起的；由于未知原因，大多数感染会在两年内消退。在这里，我们分析了 5,328 个 HPV16 阳性病例对照样本的病毒基因组，以研究突变特征以及人类 APOBEC3 诱导的突变在病毒清除和宫颈癌发生中的作用。我们确定了四种从头突变特征，其中一种与 COSMIC APOBEC 相关特征 2 相匹配。癌前期/癌症病例的病毒基因组不太可能包含宿主体细胞 HPV16 APOBEC3 诱导的突变（Fisher 精确检验，P = 6.2 x 10-14)，与对照组相比，非同义 APOBEC3 突变负担降低 30%。我们在另外 1,749 例病例中复制了 HPV16 APOBEC3 诱导突变的低患病率。 APOBEC3 突变历史上也促进了 HPV16 谱系的进化。我们证明，体细胞 HPV16 APOBEC3 诱导突变负担较大的宫颈感染更有可能是良性的或随后清除的，这表明它们可能会减少宿主体内的持续性，从而减少进展。

更新日期：2020-02-14

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