HPV‐related methylation‐based reclassification and risk stratification of cervical cancer

Abstract

Human papillomavirus (HPV) is a clear etiology of cervical cancer (CC). However, the associations between HPV infection and DNA methylation have not been thoroughly investigated. Additionally, it remains unknown whether HPV‐related methylation signatures can identify subtypes of CC and stratify the prognosis of CC patients. DNA methylation profiles were obtained from The Cancer Genome Atlas to identify HPV‐related methylation sites. Unsupervised clustering analysis of HPV‐related methylation sites was performed to determine the different CC subtypes. CC patients were categorized into cluster 1 (Methylation‐H), cluster 2 (Methylation‐M), and cluster 3 (Methylation‐L). Compared to Methylation‐M and Methylation‐L, Methylation‐H exhibited a significantly improved overall survival (OS). Gene set enrichment analysis (GSEA) was conducted to investigate the functions that correlated with different CC subtypes. GSEA indicated that the hallmarks of tumors, including KRAS signaling, TNFα signaling via NF‐κB, inflammatory response, epithelial–mesenchymal transition, and interferon‐gamma response, were enriched in Methylation‐M and Methylation‐L. Based on mutation and copy number variation analyses, we found that aberrant mutations, amplifications, and deletions among the MYC, Notch, PI3K‐AKT, and RTK‐RAS pathways were most frequently detected in Methylation‐H. Additionally, mutations, amplifications, and deletions within the Hippo, PI3K‐AKT, and TGF‐β pathways were presented in Methylation‐M. Genes within the cell cycle, Notch, and Hippo pathways possessed aberrant mutations, amplifications, and deletions in Methylation‐L. Moreover, the analysis of tumor microenvironments revealed that Methylation‐H was characterized by a relatively low degree of immune cell infiltration. Finally, a prognostic signature based on six HPV‐related methylation sites was developed and validated. Our study revealed that CC patients could be classified into three heterogeneous clusters based on HPV‐related methylation signatures. Additionally, we derived a prognostic signature using six HPV‐related methylation sites that stratified the OS of patients with CC into high‐ and low‐risk groups.

An epigenomic landscape of cervical intraepithelial neoplasia and cervical cancer using single‐base resolution methylome and hydroxymethylome

“…Hippo hijacks EGFR and HPV E6 oncoprotein to promote CC, 58 and its downstream YAP and TAZ proteins play a role in cervical tumor‐infiltrated cell activation 59 . Previously study finds that mutation, amplification, and deletions of Hippo in hypermethylated CC subgroup 60 . We provided additional evidences that methylated genes in Hippo pathway occurred in CC, even at CINs stages.…”

HPV Infection Leaves a DNA Methylation Signature in Oropharyngeal Cancer Affecting Both Coding Genes and Transposable Elements

“…HPV oncoproteins were shown to modulate DNMT1 levels [ 19 , 20 , 34 ] and some studies have been developed to identify HPV-associated alterations of DNA methylation in cervical cancer [ 35 , 36 , 37 ]. This led to the design of gene panels whose methylation levels can discriminate tumors from non-tumor tissues as well as predict preneoplastic lesions more likely to progress, with high accuracy [ 35 , 38 , 39 , 40 ]. However, in head and neck cancer, the association between HPV infection and DNA methylation aberration has been less explored, both genome-wide and in target genes.…”

Urobiome in Gender—Related Diversities of Bladder Cancer

“…It has been estimated that microbiota may be associated with more than 20% of malignancies [ 35 ], but the role of only few microorganisms as carcinogens is widely known and well established. Among the few, one has to include Helicobacter pylori (gastric cancer), Schistosoma haematobium (urinary BC), and human papilloma viruses (cervical and penile cancers) [ 36 , 37 , 38 , 39 , 40 , 41 ]. Studies of the gut, pancreatic, and breast microbiome revealed a multifactorial association between microbiota and cancer [ 35 , 42 , 43 ] and, although the mechanisms of the microbiome interaction with human cells are extremely complex, they involve at least one of these three phenomena: direct influence on host cells’ proliferation and death, modulation of innate immune system, and interaction with host biochemistry [ 44 ].…”