Abstract
Human papillomavirus (HPV) is recognised as the cause of precancerous and cancerous cervical lesions. Furthermore, in high-grade lesions, HPV is frequently integrated in the host cell genome and associated with the partial or complete loss of the E1 and E2 genes, which regulate the activity of viral oncoproteins E6 and E7. In this study, using a double-capture system followed by high-throughput sequencing, we determined the HPV integration status present in liquid-based cervical smears in an urban Gabonese population. The main inclusion criteria were based on cytological grade and the detection of the HPV16 genotype using molecular assays. The rate of HPV integration in the host genome varied with cytological grade: 85.7% (6/7), 71.4% (5/7), 66.7% (2/3) 60% (3/5) and 30.8% (4/13) for carcinomas, HSIL, ASCH, LSIL and ASCUS, respectively. For high cytological grades (carcinomas and HSIL), genotypes HPV16 and 18 represented 92.9% of the samples (13/14). The integrated form of HPV16 genotype was mainly found in high-grade lesions in 71.4% of samples regardless of cytological grade. Minority genotypes (HPV33, 51, 58 and 59) were found in LSIL samples, except HPV59, which was identified in one HSIL sample. Among all the HPV genotypes identified after double capture, 10 genotypes (HPV30, 35, 39, 44, 45, 53, 56, 59, 74 and 82) were detected only in episomal form. Our study revealed that the degree of HPV integration varies with cervical cytological grade. The integration event might be a potential clinical prognostic biomarker for the prediction of the progression of neoplastic lesions.
Highlights
Cervical cancer (CC) is the fourth most common cancer in women worldwide and is the leading cause of cancer deaths among women living in sub-Saharan Africa[1,2]
The whole-genome sequencing coupled with read mapping for analysis from DNA extracted from HeLa cell line has been used to determine that the integration event occurred near the c-myc oncogene, demonstrating an example of host chromosomal alteration caused by a viral integration associated with an cancer[17]
In this study, using a double-capture system followed by high-throughput sequencing, we determined the Human papillomavirus (HPV) genotype(s) present in liquid-based cervical (LBC) smears performed on an urban Gabonese population
Summary
Cervical cancer (CC) is the fourth most common cancer in women worldwide and is the leading cause of cancer deaths among women living in sub-Saharan Africa[1,2]. Exome sequencing can characterize HPV integration: using the blood from a metastatic cervical carcinoma patient, 1.2 billion reads were generated to detect HPV integration by mapping reads on a reference human genome This approach identified integrated HPV 18 even in the presence of the episomal form of the same HPV genotype. Another study, using the RNA-seq technique and based on discordant paired-end reads aligned to the viral and the host genomes[18], revealed an integration rate of 82.3% in cervical squamous cell carcinoma. This method can only detect integration sites within coding regions. The specific integration of HPV samples suggests that HPV integration may be a potential early-stage biological and clinical prognostic biomarker for the prediction of the progression of neoplastic lesions
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