HPV16 and HPV18 type-specific APOBEC3 and integration profiles in different diagnostic categories of cervical samples

Abstract

Human papillomavirus 16 and 18 are the most predominant types in cervical cancer. Only a small fraction of HPV infections progress to cancer, indicating that genomic factors, such as minor nucleotide variation caused by APOBEC3 and chromosomal integration, contribute to the carcinogenesis.We analysed 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 cervical cell 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 rates of MNVs in HPV16 and HPV18 samples were observed for most viral genes but for HPV16, the non-coding region (NCR) showed a trend towards increasing variation with increasing lesion severity. 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.