Characterisation of human papillomavirus genomic variation and chromosomal integration in cervical samples

Persistent infection with a high-risk human papillomavirus (HPV) type is necessary for cervical cancer development, causing nearly 5% of all cancers worldwide. Nevertheless, only a small fraction of HPV infections progress to cancer, indicating that additional molecular factors contribute to the development of cervical cancer. The thesis aimed to characterise and explore mutations in the HPV genome and viral integrations into the human genome contributing to HPV-induced carcinogenesis. This can reveal new insight into cervical cancer development. A unique next-generation sequencing protocol, TaME-seq, was developed for analysis of HPV genomic variation and integration. The results show that the overall intra-host HPV genomic variability is higher than previously assumed, with a high number of HPV genome variants found in all samples from early infections to cancer. A noticeable part of the mutations in HPV16, which is the most carcinogenic HPV type, was associated with the APOBEC3-enzyme that is suggested to be involved in viral clearance. The findings revealed integration sites that located both in previously reported and novel genomic sites. A large number of integrations was observed in or close to human cancer-related genes, which could be an indication of a more aggressive infection. The TaME-seq method could potentially be a valuable method for assessing the risk of developing cervical cancer. An additional HPV screening test would enable more personalised follow-up, improving detection of lesions with higher risk of progression and reducing unnecessary follow-up and treatment of women with minimal risk of developing high-grade lesions or cancer