A team of researchers have analysed the association between different human papilloma virus (HPV) integration signatures, clinical parameters and outcomes in pre-treated cervical cancers.
Cervical cancer
Cervical cancer remains a leading cause of gynaecological cancer-related mortality worldwide. It also constitutes the second most common malignancy in women. HPV is one of the most important risk factors for cervical cancer development. Whilst most HPV infections are cleared by the immune system, some persist and lead to cancer. Following infection, the virus can remain in its episomal form or become integrated into the host’s genome. The integration of HPV DNA mostly results in a breakpoint in the E2 gene. This causes de-repression of the E6 and E7 viral oncogenes. HPV DNA integration into the human genome catalyses various genetic alterations, such as oncogene amplification and tumour suppressor gene inactivation. Additionally, genes that are localised near the integration sites can experience changes in RNA and protein expression levels. HPV DNA integration can occur as a single copy or in multiple repeats (in tandem or dispersed).
HPV integration signature
Based on the assumption that HPV integration signatures could predict clinical outcomes, the team decided to analyse the association between the different viral integration signatures, clinical and pathological parameters and outcomes. They analysed these associations in a large cohort of 272 HPV-positive cervical cancer patients. Specifically, they used next-generation sequencing to identify different integration signatures.
Their results, published in the British Journal of Cancer, revealed >300 different HPV-chromosomal junctions. The most frequent integration site in cervical cancer was in the MACROD2 gene, followed by MIPOL1/TTC6 and TP63. Additionally, the integration signatures were not associated with histological subtype, FIGO staging and treatment of progression-free survival.
Conclusion
This is the first study to assess the prognostic value of HPV integration in a prospectively annotated cervical cancer cohort. The team’s results revealed a hotspot of HPV integration at MACROD2. This gene is involved in impaired PARP1 activity and chromosome instability. While HPV integration was thought to be a random event, these results find that some hotspots may in fact impact cancer evolution.
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