BACKGROUND Chronic infections by one of the oncogenic human papillomaviruses (HPVs) are responsible for near 5% of the global cancer burden and HPV16 is the type most often found in cancers. HPV genomes display unexpected levels of variation when deep-sequenced. Minor nucleotide variations (MNVs) may reveal HPV genomic instability and HPV-related carcinogenic transformation of host cells. OBJECTIVES The objective of this study was to investigate HPV16 genome variation at the minor variant level on persisting HPV16 cervical infections from a population of young Dutch women. STUDY DESIGN 15 HPV16 infections were sequenced using a whole-HPV genome deep sequencing protocol (TaME-seq). One infection was followed over a three-year period, eight were followed over a two-year period, three were followed over a one-year period and three infections had a single sampling point. RESULTS AND CONCLUSIONS Using a 1% variant frequency cutoff, we find on average 48 MNVs per HPV16 genome and 1717 MNVs in total when sequencing coverage was >100 × . We find the transition mutation T > C to be the most common, in contrast to other studies detecting APOBEC-related C > T mutation profiles in pre-cancerous and cancer samples. Our results suggest that the relative mutagenic footprint of HPV16 genomes may differ between the infections in this study and transforming lesions. In addition, we identify a number of MNVs that have previously been associated with higher incidence of high-grade lesions (CIN3+) in a population study. These findings may provide a starting point for future studies exploring causality between emerging HPV minor genomic variants and cancer development.

中文翻译：

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荷兰年轻女性持续感染的HPV16全基因组少数变异。

背景技术由致癌性人乳头瘤病毒（HPV）之一引起的慢性感染占全球癌症负担的近5％，HPV16是在癌症中最常见的类型。深度测序时，HPV基因组显示出意想不到的变异水平。较小的核苷酸变异（MNV）可能揭示宿主细胞的HPV基因组不稳定性和HPV相关的致癌转化。目的本研究的目的是研究荷兰年轻女性人群中持续存在的HPV16子宫颈感染对HPV16基因组变异的影响。研究设计使用全HPV基因组深度测序方案（TaME-seq）对15株HPV16感染进行了测序。在三年内进行了一次感染，在两年内进行了八次感染，在一年的时间里跟踪了三例，并且三个感染有一个采样点。结果与结论使用1％的变异频率截止，当测序覆盖率> 100×时，我们发现每个HPV16基因组平均48个MNV，总共1717个MNV。我们发现过渡突变T> C是最常见的，这与其他研究在癌前和癌变样本中检测与APOBEC相关的C> T突变谱的研究相反。我们的结果表明，HPV16基因组的相对诱变足迹可能在本研究中的感染与转化病灶之间有所不同。此外，我们在人群研究中发现了许多先前与高级别病变（CIN3 +）发生率相关的MNV。