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Identification of recurrent FHL2-GLI2 oncogenic fusion in sclerosing stromal tumors of the ovary

Author

Listed:
  • Sarah H. Kim

    (Memorial Sloan Kettering Cancer Center)

  • Arnaud Da Cruz Paula

    (Memorial Sloan Kettering Cancer Center)

  • Thais Basili

    (Memorial Sloan Kettering Cancer Center)

  • Higinio Dopeso

    (Memorial Sloan Kettering Cancer Center)

  • Rui Bi

    (Memorial Sloan Kettering Cancer Center
    Fudan University Shanghai Cancer Center)

  • Fresia Pareja

    (Memorial Sloan Kettering Cancer Center)

  • Edaise M. Silva

    (Memorial Sloan Kettering Cancer Center)

  • Rodrigo Gularte-Mérida

    (Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center)

  • Zhen Sun

    (Memorial Sloan Kettering Cancer Center)

  • Sho Fujisawa

    (Memorial Sloan Kettering Cancer Center)

  • Caitlin G. Smith

    (Memorial Sloan Kettering Cancer Center)

  • Lorenzo Ferrando

    (Memorial Sloan Kettering Cancer Center
    University of Genoa)

  • Ana Paula Martins Sebastião

    (Memorial Sloan Kettering Cancer Center
    Federal University of Paraná)

  • Yonina Bykov

    (Memorial Sloan Kettering Cancer Center)

  • Anqi Li

    (Memorial Sloan Kettering Cancer Center
    Fudan University Shanghai Cancer Center)

  • Catarina Silveira

    (Memorial Sloan Kettering Cancer Center
    University of Lisbon)

  • Charles W. Ashley

    (Memorial Sloan Kettering Cancer Center)

  • Anthe Stylianou

    (Memorial Sloan Kettering Cancer Center)

  • Pier Selenica

    (Memorial Sloan Kettering Cancer Center)

  • Wesley R. Samore

    (Massachusetts General Hospital, Harvard Medical School)

  • Achim A. Jungbluth

    (Memorial Sloan Kettering Cancer Center)

  • Dmitriy Zamarin

    (Memorial Sloan Kettering Cancer Center)

  • Nadeem R. Abu-Rustum

    (Memorial Sloan Kettering Cancer Center)

  • Kristian Helin

    (Memorial Sloan Kettering Cancer Center
    University of Copenhagen
    University of Copenhagen)

  • Robert A. Soslow

    (Memorial Sloan Kettering Cancer Center)

  • Jorge S. Reis-Filho

    (Memorial Sloan Kettering Cancer Center)

  • Esther Oliva

    (Massachusetts General Hospital, Harvard Medical School)

  • Britta Weigelt

    (Memorial Sloan Kettering Cancer Center)

Abstract

Sclerosing stromal tumor (SST) of the ovary is a rare type of sex cord-stromal tumor (SCST), whose genetic underpinning is currently unknown. Here, using whole-exome, targeted capture and RNA-sequencing, we report recurrent FHL2-GLI2 fusion genes in 65% (17/26) of SSTs and other GLI2 rearrangements in additional 15% (4/26) SSTs, none of which are detected in other types of SCSTs (n = 48) or common cancer types (n = 9,950). The FHL2-GLI2 fusions result in transcriptomic activation of the Sonic Hedgehog (SHH) pathway in SSTs. Expression of the FHL2-GLI2 fusion in vitro leads to the acquisition of phenotypic characteristics of SSTs, increased proliferation, migration and colony formation, and SHH pathway activation. Targeted inhibition of the SHH pathway results in reversal of these oncogenic properties, indicating its role in the pathogenesis of SSTs. Our results demonstrate that the FHL2-GLI2 fusion is likely the oncogenic driver of SSTs, defining a genotypic–phenotypic correlation in ovarian neoplasms.

Suggested Citation

  • Sarah H. Kim & Arnaud Da Cruz Paula & Thais Basili & Higinio Dopeso & Rui Bi & Fresia Pareja & Edaise M. Silva & Rodrigo Gularte-Mérida & Zhen Sun & Sho Fujisawa & Caitlin G. Smith & Lorenzo Ferrando , 2020. "Identification of recurrent FHL2-GLI2 oncogenic fusion in sclerosing stromal tumors of the ovary," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-13806-x
    DOI: 10.1038/s41467-019-13806-x
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