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Analysis of Ugandan cervical carcinomas identifies human papillomavirus clade-specific epigenome and transcriptome landscapes.

3 August 2020; 10.1038/s41588-020-0673-7

Cervical cancer is the most common cancer affecting sub-Saharan African women. Persistent human papillomavirus (HPV) infection is necessary but not sufficient for the development of cervical cancer. Cervical cancer is considered to be an AIDS-defining malignancy as it is 5 times more likely to develop in HIV-positive (HIV+) women than in those that are HIV-negative (HIV-). The Human Tumor Molecular Characterization Project performed comprehensive profiling of cancer genomes, transcriptomes, or epigenomes to fill the knowledge gap in this population. We characterized 118 tumors from East-African patients, of which 72 were HIV+, and performed extended mutation analysis on an additional 89 cases, 16 of which were HIV+. Of 12 significantly mutated genes in our cohort, PIK3CA was the most recurrent as reported in other studies. Some genes which were mutated in other cohorts were not in ours. Analysis of copy number landscapes revealed that broad copy number alterations were comparable between HIV+ and HIV- samples. We detected HPV clade-specific differences in tumor DNA methylation, promoter- and enhancer-associated histone marks, gene expression and pathway dysregulation. Histone modification changes at HPV integration events were correlated with upregulation of nearby genes and endogenous retroviruses.

To probe the impact of viral gene expression on tumor gene expression, we performed unsupervised clustering of viral E1,E2, E6, and E7 transcripts which had annotations associated with them in GenBank (download date: December 2019). A list of these references can be accessed via the “CGCI HTMCP-CC HPV Transcript References (December 2019)” link in the “Supplemental Data” section below.

This study characterized CGCI cases as described below:

118 Discovery Cases 89 Validation Cases 5 Excluded Cases*
118 cases - mRNA-seq 89 cases - Targeted Capture Sequencing 5 cases - mRNA-seq
113 cases - miRNA-seq   5 cases - miRNA-seq
115 cases - Methylation Array   5 cases - Methylation Array
52 cases - ChIP-Seq   5 cases - WGS
118 cases - WGS    

* 5 cases were excluded from the study because it was determined that they did not have cervical cancer, but instead had uterine or endometrial cancer. Data related to these excluded cases was still submitted as part of this publication.

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