HPV Clade Affects Cervical Cancer Genome, Transcriptome, and Epigenome

Infection with human papillomavirus (HPV) is the principal driver of cervical cancer, the most common malignancy among women in sub-Saharan Africa, and more than 70% of cervical cancers harbor persistent infection with HPV-16 (a member of clade A9) or HPV-18 (a member of clade A7). HPV-16 and HPV-18 infection confer different prognoses, but how infection with either strain affects the cancer genome, epigenome, and transcriptome has not been established. To gain a better understanding, Gagliardi, Porter, Zong, Bowlby, Titmuss, and colleagues analyzed 118 tumors from patients from Uganda, including 72 who were HIV⁺. Among these 118 tumors, 57 harbored clade-A9 HPV, 52 harbored clade-A7 HPV (known to confer worse prognosis), and the remaining 9 harbored HPV of other clades. A transcriptomic analysis revealed that cells from tumors with clade-A7 HPV differentially expressed genes involved in organization of the extracellular matrix, cell adhesion, and cell migration, consistent with their predicted and observed more aggressive phenotype and possibly caused by observed differences in DNA methylation. Additional epigenomic analyses identified HPV clade–specific differences in histone modifications, with clade A7–infected samples having increased histone 3 lysine residue 4 methylation (H3K4me1, which is associated with enhancers) and histone 3 lysine residue 27 acetylation (H3K27ac, which is associated with active promoters) and clade A9–infected samples having increased histone 3 lysine residue 4 trimethylation (H3K4me3, which is associated with active promoters). These epigenetic variations affected expression of genes with potential functional relevance; for example, in samples infected with the tumor aggressiveness–associated clade A7 HPV, genes related to invasion and the extracellular matrix were upregulated. Notably, HPV integration sites were associated with alterations to the modifications of nearby histones and, consequently, altered gene expression, with one such example being frequent upregulation of ERBB2 (encoding the proto-oncoprotein HER2). Collectively, this work supplies an in-depth genomic, transcriptomic, and epigenomic characterization of cervical cancer in patients from Uganda, providing insight into the molecular features of cervical cancer in people of this understudied ancestry.

Gagliardi A, Porter VL, Zong Z, Bowlby R, Titmuss E, Namirembe C, et al. Analysis of Ugandan cervical carcinomas identifies human papillomavirus clade–specific epigenome and transcriptome landscapes. Nat Genet 2020;52:800–10.

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.