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

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

doi:10.1038/s41467-020-15951-0

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

Nat Commun. 2020 Apr 24;11(1):2020. doi: 10.1038/s41467-020-15951-0.

Authors

Rosario I Corona^#^{1

2}, Ji-Heui Seo^#^{3

4}, Xianzhi Lin^#¹, Dennis J Hazelett², Jessica Reddy¹, Marcos A S Fonseca¹, Forough Abassi¹, Yvonne G Lin⁵, Paulette Y Mhawech-Fauceglia⁶, Sohrab P Shah^{7

8

9}, David G Huntsman^{8

9

10}, Alexander Gusev^{3

11}, Beth Y Karlan¹, Benjamin P Berman², Matthew L Freedman^{12

13

14}, Simon A Gayther^{15

16}, Kate Lawrenson^{17

18}

Affiliations

¹ Cedars-Sinai Women's Cancer Program at the Samuel Oschin Cancer Center, Los Angeles, CA, USA.
² Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
³ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁴ Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.
⁵ Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁶ Department of Pathology, University of Southern California, Los Angeles, CA, USA.
⁷ Department of Computer Science, University of British Columbia, Vancouver, BC, Canada.
⁸ Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC, Canada.
⁹ Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
¹⁰ Department of Gynecology and Obstetrics, University of British Columbia, Vancouver, BC, Canada.
¹¹ McGraw/Patterson Center for Population Sciences, Dana-Farber Cancer Institute, Boston, MA, USA.
¹² Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
¹³ Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
¹⁴ The Eli and Edythe L. Broad Institute, Cambridge, MA, USA. [email protected].
¹⁵ Cedars-Sinai Women's Cancer Program at the Samuel Oschin Cancer Center, Los Angeles, CA, USA. [email protected].
¹⁶ Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA. [email protected].
¹⁷ Cedars-Sinai Women's Cancer Program at the Samuel Oschin Cancer Center, Los Angeles, CA, USA. [email protected].
¹⁸ Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA. [email protected].

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Binding Sites / genetics
Carcinoma, Ovarian Epithelial / genetics*
Carcinoma, Ovarian Epithelial / pathology
Chromatin Immunoprecipitation Sequencing
DNA-Binding Proteins / metabolism
Enhancer Elements, Genetic
Epigenesis, Genetic
Epigenomics
Female
Gene Expression Regulation, Neoplastic*
Gene Knockout Techniques
Gene Regulatory Networks*
Humans
Kruppel-Like Transcription Factors / genetics
Middle Aged
Muscle Proteins / metabolism
Mutation
Ovarian Neoplasms / genetics*
Ovarian Neoplasms / pathology
Ovary / pathology
PAX8 Transcription Factor / metabolism*
Polymorphism, Single Nucleotide
RNA-Seq
Repressor Proteins / genetics
TEA Domain Transcription Factors
Transcription Factors / metabolism
Whole Genome Sequencing

Substances

DNA-Binding Proteins
Kruppel-Like Transcription Factors
Muscle Proteins
PAX8 Transcription Factor
PAX8 protein, human
Repressor Proteins
TEA Domain Transcription Factors
TEAD4 protein, human
Transcription Factors
ZSCAN12 protein, human
ZSCAN16 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding