Genomic, transcriptomic, and viral integration profiles associated with recurrent/metastatic progression in high‐risk human papillomavirus cervical carcinomas

作者：Jing Jing Liu, Sung Min Yoon, Jung Eum Lee, Soo Young Hur, Jinseon Yoo, Kyu Ryung Kim, Daeun Ryu, Tae‐Min Kim, Youn Jin Choi · 发表于：Cancer Medicine · 年份：2020 · DOI：10.1002/cam4.3426 · 被引用次数：8 · 研究领域：Cervical Cancer and HPV Research、Cancer Genomics and Diagnostics、Cancer Immunotherapy and Biomarkers

Acquisition of recurrent/metastatic potential by a tumor cell defines a critical step in malignant progression. However, understanding of metastatic progression at the molecular level is scarce for cervical carcinomas (CES). In this study, we performed genomic, transcriptomic, and viral profiling of five pairs of primary (CES-P) and matched recurrent/metastatic tumors (CES-R/M) with high risk human papillomavirus. Whole exome sequencing revealed mutation features of CES-R/M including elevated mutation burdens and prevalent copy number alterations compared to their matched CES-P. A relative deficit of APOBEC-related mutation signatures accompanying the transcriptional downregulation of APOBEC3A was observed for CES-R/M. Mutations in genes encoding epigenetic regulators were commonly observed as CES-R/M-specific alterations. Immunoprofiling and gene set analysis revealed CES-Ps were enriched with transcripts representing activated anticancer immunity such as interferon-gamma pathway, while CES-R/M exhibited upregulation of genes involved in epithelial-mesenchymal transition and angiogenesis. Viral capture sequencing revealed that integration sites remained enriched in viral E1 protein domain during malignant progression. Moreover, we found transcriptional upregulation of POSTN and downregulation of APOBEC3A were associated with unfavorable clinical outcomes in CES. Comprehensive genomic and transcriptomic profiling of a rare cohort including CES-R/M identified metastases-specif...