Non-coding somatic mutations converge on the PAX8 pathway in ovarian cancer

被引：0

作者：

Rosario I. Corona

Ji-Heui Seo

Xianzhi Lin

Dennis J. Hazelett

Jessica Reddy

Marcos A. S. Fonseca

Forough Abassi

Yvonne G. Lin

Paulette Y. Mhawech-Fauceglia

Sohrab P. Shah

David G. Huntsman

Alexander Gusev

Beth Y. Karlan

Benjamin P. Berman

Matthew L. Freedman

Simon A. Gayther

Kate Lawrenson

机构：

[1] Cedars-Sinai Women’s Cancer Program at the Samuel Oschin Cancer Center,Center for Bioinformatics and Functional Genomics

[2] Cedars-Sinai Medical Center,Department of Medical Oncology

[3] Dana-Farber Cancer Institute,Center for Functional Cancer Epigenetics

[4] Dana-Farber Cancer Institute,Department of Obstetrics and Gynecology, Keck School of Medicine

[5] University of Southern California,Department of Pathology

[6] University of Southern California,Department of Computer Science

[7] University of British Columbia,Department of Molecular Oncology

[8] BC Cancer Agency,Department of Pathology and Laboratory Medicine

[9] University of British Columbia,Department of Gynecology and Obstetrics

[10] University of British Columbia,McGraw/Patterson Center for Population Sciences

[11] Dana-Farber Cancer Institute,undefined

[12] The Eli and Edythe L. Broad Institute,undefined

来源：

Nature Communications | / 11卷

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摘要：

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.

引用

共 62 条

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