1. Non-coding somatic mutations converge on the PAX8 pathway in ovarian cancer.
- Author
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Corona, Rosario I, Seo, Ji-Heui, Lin, Xianzhi, Hazelett, Dennis J, Reddy, Jessica, Fonseca, Marcos AS, Abassi, Forough, Lin, Yvonne G, Mhawech-Fauceglia, Paulette Y, Shah, Sohrab P, Huntsman, David G, Gusev, Alexander, Karlan, Beth Y, Berman, Benjamin P, Freedman, Matthew L, Gayther, Simon A, and Lawrenson, Kate
- Subjects
Ovary ,Humans ,Ovarian Neoplasms ,Muscle Proteins ,DNA-Binding Proteins ,Transcription Factors ,Repressor Proteins ,Epigenesis ,Genetic ,Gene Expression Regulation ,Neoplastic ,Binding Sites ,Mutation ,Polymorphism ,Single Nucleotide ,Adult ,Aged ,Middle Aged ,Female ,Kruppel-Like Transcription Factors ,Gene Regulatory Networks ,Enhancer Elements ,Genetic ,Gene Knockout Techniques ,Epigenomics ,PAX8 Transcription Factor ,Whole Genome Sequencing ,Carcinoma ,Ovarian Epithelial ,Chromatin Immunoprecipitation Sequencing ,RNA-Seq - Abstract
The functional consequences of somatic non-coding mutations in ovarian cancer (OC) are unknown. To identify regulatory elements (RE) and genes perturbed by acquired non-coding variants, here we establish epigenomic and transcriptomic landscapes of primary OCs using H3K27ac ChIP-seq and RNA-seq, and then integrate these with whole genome sequencing data from 232 OCs. We identify 25 frequently mutated regulatory elements, including an enhancer at 6p22.1 which associates with differential expression of ZSCAN16 (P = 6.6 × 10-4) and ZSCAN12 (P = 0.02). CRISPR/Cas9 knockout of this enhancer induces downregulation of both genes. Globally, there is an enrichment of single nucleotide variants in active binding sites for TEAD4 (P = 6 × 10-11) and its binding partner PAX8 (P = 2×10-10), a known lineage-specific transcription factor in OC. In addition, the collection of cis REs associated with PAX8 comprise the most frequently mutated set of enhancers in OC (P = 0.003). These data indicate that non-coding somatic mutations disrupt the PAX8 transcriptional network during OC development.
- Published
- 2020