Diverse tumorigenic consequences of human papillomavirus integration in primary oropharyngeal cancers.

Human papillomavirus (HPV) causes 5% of all cancers and frequently integrates into host chromosomes. The HPV oncoproteins E6 and E7 are necessary but insufficient for cancer formation, indicating that additional secondary genetic events are required. Here, we investigate potential oncogenic impacts of virus integration. Analysis of 105 HPV-positive oropharyngeal cancers by whole-genome sequencing detects virus integration in 77%, revealing five statistically significant sites of recurrent integration near genes that regulate epithelial stem cell maintenance (i.e., SOX2, TP63, FGFR, MYC) and immune evasion (i.e., CD274). Genomic copy number hyperamplification is enriched 16-fold near HPV integrants, and the extent of focal host genomic instability increases with their local density. The frequency of genes expressed at extreme outlier levels is increased 86-fold within ±150 kb of integrants. Across 95% of tumors with integration, host gene transcription is disrupted via intragenic integrants, chimeric transcription, outlier expression, gene breaking, and/or de novo expression of noncoding or imprinted genes. We conclude that virus integration can contribute to carcinogenesis in a large majority of HPV-positive oropharyngeal cancers by inducing extensive disruption of host genome structure and gene expression.

Systems analysis of the effects of the 2014-16 Ebola crisis on WHO-reporting nations' policy adaptations and 2020-21 COVID-19 response: a systematized review.

BACKGROUND: Recent case studies indicate that the 2014-2016 Ebola outbreak, one of the worst pre-2020 global biological catastrophes in modern history, helped some nations to better prepared their responses for the COVID-19 pandemic. While such national case studies explore how specific nations applied EVD-related policies in their domestic battle against the COVID-19 pandemic, there is no known study that assesses how many WHO nations learned from the West African crisis and to what scale. OBJECTIVE: Applying the policy legacies analytical framework and a systematized literature review, this research examines how prior policy experiences with the 2014-16 EVD crisis as a large-scale emergent outbreak helped to inform and to condition WHO nations to proactively prepare their national policies and health systems for future threats, including ultimately COVID-19. METHODS: A systematized literature review of 803 evaluated sources assesses to what extent Ebola-affected and non-affected nations directly modified governmental health systems in relation to this warning. The study further evaluates how nations with documented Ebola-related changes fared during COVID-19 compared to nations that did not. We present a categorical theoretical framework that allows for classifying different types of national response activities (termed conditioned learning). RESULTS: Ten (90.9%) of 11 nations that were affected by 2014-16 Ebola crisis have documented evidence of repurposing their EVD-related policies to fight COVID-19. 164 (70.0%) of 234 non-EVD-affected nations had documented evidence of specifically adapting national systems to incorporate policy recommendations developed from the 2014-16 crisis, which informed their COVID-19 responses in 2020. CONCLUSIONS: The shock of 2014-16 EVD outbreak affected most nations around the world, whether they experienced Ebola cases. We further develop a categorical framework that helps characterised nations previous experiences with this biological catastrophe, providing a means to analyse to what extent that individual nations learned and how these EVD-related changes helped inform their COVID-19 response. Nations that demonstrated EVD-related conditioned learning nations tended to have more stringent COVID-19 responses before April 2020 and utilized documented response mechanisms developed out of the West African crisis.