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

Author

Listed:
  • Rosario I. Corona

    (Cedars-Sinai Women’s Cancer Program at the Samuel Oschin Cancer Center
    Cedars-Sinai Medical Center)

  • Ji-Heui Seo

    (Dana-Farber Cancer Institute
    Dana-Farber Cancer Institute)

  • Xianzhi Lin

    (Cedars-Sinai Women’s Cancer Program at the Samuel Oschin Cancer Center)

  • Dennis J. Hazelett

    (Cedars-Sinai Medical Center)

  • Jessica Reddy

    (Cedars-Sinai Women’s Cancer Program at the Samuel Oschin Cancer Center)

  • Marcos A. S. Fonseca

    (Cedars-Sinai Women’s Cancer Program at the Samuel Oschin Cancer Center)

  • Forough Abassi

    (Cedars-Sinai Women’s Cancer Program at the Samuel Oschin Cancer Center)

  • Yvonne G. Lin

    (University of Southern California)

  • Paulette Y. Mhawech-Fauceglia

    (University of Southern California)

  • Sohrab P. Shah

    (University of British Columbia
    BC Cancer Agency
    University of British Columbia)

  • David G. Huntsman

    (BC Cancer Agency
    University of British Columbia
    University of British Columbia)

  • Alexander Gusev

    (Dana-Farber Cancer Institute
    Dana-Farber Cancer Institute)

  • Beth Y. Karlan

    (Cedars-Sinai Women’s Cancer Program at the Samuel Oschin Cancer Center)

  • Benjamin P. Berman

    (Cedars-Sinai Medical Center)

  • Matthew L. Freedman

    (Dana-Farber Cancer Institute
    Dana-Farber Cancer Institute
    The Eli and Edythe L. Broad Institute)

  • Simon A. Gayther

    (Cedars-Sinai Women’s Cancer Program at the Samuel Oschin Cancer Center
    Cedars-Sinai Medical Center)

  • Kate Lawrenson

    (Cedars-Sinai Women’s Cancer Program at the Samuel Oschin Cancer Center
    Cedars-Sinai Medical Center)

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.

Suggested Citation

  • 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. H, 2020. "Non-coding somatic mutations converge on the PAX8 pathway in ovarian cancer," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15951-0
    DOI: 10.1038/s41467-020-15951-0
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    Cited by:

    1. Michael R. Kelly & Kamila Wisniewska & Matthew J. Regner & Michael W. Lewis & Andrea A. Perreault & Eric S. Davis & Douglas H. Phanstiel & Joel S. Parker & Hector L. Franco, 2022. "A multi-omic dissection of super-enhancer driven oncogenic gene expression programs in ovarian cancer," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    2. Roberta Esposito & Andrés Lanzós & Tina Uroda & Sunandini Ramnarayanan & Isabel Büchi & Taisia Polidori & Hugo Guillen-Ramirez & Ante Mihaljevic & Bernard Mefi Merlin & Lia Mela & Eugenio Zoni & Lusin, 2023. "Tumour mutations in long noncoding RNAs enhance cell fitness," Nature Communications, Nature, vol. 14(1), pages 1-21, December.

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