Sonja Lagström , Alexander Hesselberg Løvestad , Sinan Uğur Umu , Ole Herman Ambur , Mari Nygård , Trine B. Rounge , Irene Kraus Christiansen
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引用次数: 10
Abstract
Human papillomavirus (HPV) 16 and 18 are the most predominant types in cervical cancer. Only a small fraction of HPV infections progress to cancer, indicating that additional factors and genomic events contribute to the carcinogenesis, such as minor nucleotide variation caused by APOBEC3 and chromosomal integration.
We analysed intra-host minor nucleotide variants (MNVs) and integration in HPV16 and HPV18 positive cervical samples with different morphology. Samples were sequenced using an HPV whole genome sequencing protocol TaME-seq. A total of 80 HPV16 and 51 HPV18 positive samples passed the sequencing depth criteria of 300× reads, showing the following distribution: non-progressive disease (HPV16 n = 21, HPV18 n = 12); cervical intraepithelial neoplasia (CIN) grade 2 (HPV16 n = 27, HPV18 n = 9); CIN3/adenocarcinoma in situ (AIS) (HPV16 n = 27, HPV18 n = 30); cervical cancer (HPV16 n = 5).
Similar numbers of MNVs in HPV16 and HPV18 samples were observed for most viral genes, with the exception of HPV18 E4 with higher numbers across clinical categories. APOBEC3 signatures were observed in HPV16 lesions, while similar mutation patterns were not detected for HPV18. The proportion of samples with integration was 13% for HPV16 and 59% for HPV18 positive samples, with a noticeable portion located within or close to cancer-related genes.
人乳头瘤病毒(HPV) 16和18是宫颈癌中最主要的类型。只有一小部分HPV感染进展为癌症,表明其他因素和基因组事件有助于致癌,如APOBEC3和染色体整合引起的小核苷酸变异。我们分析了不同形态的HPV16和HPV18阳性宫颈样本的宿主内小核苷酸变异(mnv)和整合。使用HPV全基因组测序方案TaME-seq对样本进行测序。共有80份HPV16和51份HPV18阳性样本通过了300x reads的测序深度标准,其分布如下:非进展性疾病(HPV16 n = 21, HPV18 n = 12);宫颈上皮内肿瘤(CIN) 2级(HPV16 n = 27, HPV18 n = 9);CIN3/原位腺癌(AIS) (HPV16 n = 27, HPV18 n = 30);在HPV16和HPV18样本中,大多数病毒基因的mnv数量相似,但HPV18 E4的mnv数量在临床类别中较高。在HPV16病变中观察到APOBEC3特征,而在HPV18病变中未检测到类似的突变模式。HPV16和HPV18阳性样本整合的比例分别为13%和59%,其中显著部分位于或接近癌症相关基因。