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.
Nat Commun. 2020 Feb 14;11(1):886. doi: 10.1038/s41467-020-14730-1.
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), 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.
HPV16 导致全球一半的宫颈癌；由于未知原因，大多数感染在两年内得到解决。在这里，我们分析了 5328 例 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。我们确定了四个新的突变特征，其中一个与 COSMIC APOBEC 相关的特征 2 相匹配。癌前/癌症病例的病毒基因组中不太可能包含体内 HPV16 APOBEC3 诱导的突变（Fisher 精确检验，P = 6.2 x 10），与对照组相比，非同义 APOBEC3 突变负担低 30%。我们在另外 1749 例病例中复制了 HPV16 APOBEC3 诱导突变的低发生率。APOBEC3 突变也在 HPV16 谱系的进化中起到了历史作用。我们证明，具有更高负担的体细胞 HPV16 APOBEC3 诱导突变的宫颈感染更可能是良性的或随后清除的，这表明它们可能减少了在宿主中的持续存在，从而减少了进展。
