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

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

29 Scopus citations

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.

Original language	American English
Article number	2020
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-15951-0
State	Published - 1 Dec 2020
Externally published	Yes

Bibliographical note

Funding Information:
This work was supported by a Tower Cancer Research Foundation Career Development Award and a K99/R00 grant from the National Cancer Institute (NCI) (1K99CA184415-01), both to K.L. K.L. is supported in part by a Liz Tilberis Award from the Ovarian Cancer Research Alliance (OCRA, Grant number 599175). The tissue specimens were either collected as part of the USC Jean Richardson Gynecologic Tissue and Fluid Repository, which is supported by a grant from the USC Department of Obstetrics & Gynecology and the NCT Cancer Center Shared Grant award P30 CA014089 (to the Norris Comprehensive Cancer Center) or as part of the Women’s Cancer Biobank at Cedars-Sinai Medical Center. This work was supported in part by the Ovarian Cancer Research Fund Alliance Program Project Development Grant (373356): Co-Evolution of Epithelial Ovarian Cancer and Tumor Stroma (B.Y.K., K.L.). Part of these data were from the PanCancer Analysis of Whole Genomes (PCAWG) project [https://dcc.icgc.org/ pcawg].

Publisher Copyright:
© 2020, The Author(s).

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10.1038/s41467-020-15951-0

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Corona, R. I., Seo, J. H., Lin, X., Hazelett, D. J., Reddy, J., Fonseca, M. A. S., Abassi, F., Lin, Y. G., Mhawech-Fauceglia, P. Y., Shah, S. P., Huntsman, D. G., Gusev, A., Karlan, B. Y., Berman, B. P., Freedman, M. L., Gayther, S. A., & Lawrenson, K. (2020). Non-coding somatic mutations converge on the PAX8 pathway in ovarian cancer. Nature Communications, 11(1), Article 2020. https://doi.org/10.1038/s41467-020-15951-0

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title = "Non-coding somatic mutations converge on the PAX8 pathway in ovarian cancer",

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.",

author = "Corona, {Rosario I.} and Seo, {Ji Heui} and Xianzhi Lin and Hazelett, {Dennis J.} and Jessica Reddy and Fonseca, {Marcos A.S.} and Forough Abassi and Lin, {Yvonne G.} and Mhawech-Fauceglia, {Paulette Y.} and Shah, {Sohrab P.} and Huntsman, {David G.} and Alexander Gusev and Karlan, {Beth Y.} and Berman, {Benjamin P.} and Freedman, {Matthew L.} and Gayther, {Simon A.} and Kate Lawrenson",

note = "Funding Information: This work was supported by a Tower Cancer Research Foundation Career Development Award and a K99/R00 grant from the National Cancer Institute (NCI) (1K99CA184415-01), both to K.L. K.L. is supported in part by a Liz Tilberis Award from the Ovarian Cancer Research Alliance (OCRA, Grant number 599175). The tissue specimens were either collected as part of the USC Jean Richardson Gynecologic Tissue and Fluid Repository, which is supported by a grant from the USC Department of Obstetrics & Gynecology and the NCT Cancer Center Shared Grant award P30 CA014089 (to the Norris Comprehensive Cancer Center) or as part of the Women{\textquoteright}s Cancer Biobank at Cedars-Sinai Medical Center. This work was supported in part by the Ovarian Cancer Research Fund Alliance Program Project Development Grant (373356): Co-Evolution of Epithelial Ovarian Cancer and Tumor Stroma (B.Y.K., K.L.). Part of these data were from the PanCancer Analysis of Whole Genomes (PCAWG) project [https://dcc.icgc.org/ pcawg]. Publisher Copyright: {\textcopyright} 2020, The Author(s).",

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doi = "10.1038/s41467-020-15951-0",

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Corona, RI, Seo, JH, Lin, X, Hazelett, DJ, Reddy, J, Fonseca, MAS, Abassi, F, Lin, YG, Mhawech-Fauceglia, PY, Shah, SP, Huntsman, DG, Gusev, A, Karlan, BY, Berman, BP, Freedman, ML, Gayther, SA & Lawrenson, K 2020, 'Non-coding somatic mutations converge on the PAX8 pathway in ovarian cancer', Nature Communications, vol. 11, no. 1, 2020. https://doi.org/10.1038/s41467-020-15951-0

TY - JOUR

T1 - Non-coding somatic mutations converge on the PAX8 pathway in ovarian cancer

AU - Corona, Rosario I.

AU - Seo, Ji Heui

AU - Lin, Xianzhi

AU - Hazelett, Dennis J.

AU - Reddy, Jessica

AU - Fonseca, Marcos A.S.

AU - Abassi, Forough

AU - Lin, Yvonne G.

AU - Mhawech-Fauceglia, Paulette Y.

AU - Shah, Sohrab P.

AU - Huntsman, David G.

AU - Gusev, Alexander

AU - Karlan, Beth Y.

AU - Berman, Benjamin P.

AU - Freedman, Matthew L.

AU - Gayther, Simon A.

AU - Lawrenson, Kate

N1 - Funding Information: This work was supported by a Tower Cancer Research Foundation Career Development Award and a K99/R00 grant from the National Cancer Institute (NCI) (1K99CA184415-01), both to K.L. K.L. is supported in part by a Liz Tilberis Award from the Ovarian Cancer Research Alliance (OCRA, Grant number 599175). The tissue specimens were either collected as part of the USC Jean Richardson Gynecologic Tissue and Fluid Repository, which is supported by a grant from the USC Department of Obstetrics & Gynecology and the NCT Cancer Center Shared Grant award P30 CA014089 (to the Norris Comprehensive Cancer Center) or as part of the Women’s Cancer Biobank at Cedars-Sinai Medical Center. This work was supported in part by the Ovarian Cancer Research Fund Alliance Program Project Development Grant (373356): Co-Evolution of Epithelial Ovarian Cancer and Tumor Stroma (B.Y.K., K.L.). Part of these data were from the PanCancer Analysis of Whole Genomes (PCAWG) project [https://dcc.icgc.org/ pcawg]. Publisher Copyright: © 2020, The Author(s).

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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.

AB - 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.

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U2 - 10.1038/s41467-020-15951-0

DO - 10.1038/s41467-020-15951-0

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SN - 2041-1723

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JO - Nature Communications

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IS - 1

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ER -

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

Abstract

Bibliographical note

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