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

Sarah H. Kim; Arnaud Da Cruz Paula; Thais Basili; Higinio Dopeso; Rui Bi; Fresia Pareja; Edaise M. da Silva; Rodrigo Gularte-Mérida; Zhen Sun; Sho Fujisawa; Caitlin G. Smith; Lorenzo Ferrando; Ana Paula Martins Sebastião; Yonina Bykov; Anqi Li; Catarina Silveira; Charles W. Ashley; Anthe Stylianou; Pier Selenica; Wesley R. Samore; Achim A. Jungbluth; Dmitriy Zamarin; Nadeem R. Abu-Rustum; Kristian Helin; Robert A. Soslow; Jorge S. Reis-Filho; Esther Oliva; Britta Weigelt

doi:10.1038/s41467-019-13806-x

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

Sarah H. Kim, Arnaud Da Cruz Paula, Thais Basili, Higinio Dopeso, Rui Bi, Fresia Pareja, Edaise M. da Silva, Rodrigo Gularte-Mérida, Zhen Sun, Sho Fujisawa, Caitlin G. Smith, Lorenzo Ferrando, Ana Paula Martins Sebastião, Yonina Bykov, Anqi Li, Catarina Silveira, Charles W. Ashley, Anthe Stylianou, Pier Selenica, Wesley R. SamoreAchim A. Jungbluth, Dmitriy Zamarin, Nadeem R. Abu-Rustum, Kristian Helin, Robert A. Soslow, Jorge S. Reis-Filho, Esther Oliva, Britta Weigelt

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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.

Original language	English
Article number	44
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-13806-x
State	Published - 1 Dec 2020
Externally published	Yes

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Kim, S. H., Da Cruz Paula, A., Basili, T., Dopeso, H., Bi, R., Pareja, F., da Silva, E. M., Gularte-Mérida, R., Sun, Z., Fujisawa, S., Smith, C. G., Ferrando, L., Martins Sebastião, A. P., Bykov, Y., Li, A., Silveira, C., Ashley, C. W., Stylianou, A., Selenica, P., ... Weigelt, B. (2020). Identification of recurrent FHL2-GLI2 oncogenic fusion in sclerosing stromal tumors of the ovary. Nature Communications, 11(1), Article 44. https://doi.org/10.1038/s41467-019-13806-x

@article{d22dbadd4c65457c9dabf2661c304e92,

title = "Identification of recurrent FHL2-GLI2 oncogenic fusion in sclerosing stromal tumors of the ovary",

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.",

author = "Kim, {Sarah H.} and {Da Cruz Paula}, Arnaud and Thais Basili and Higinio Dopeso and Rui Bi and Fresia Pareja and {da Silva}, {Edaise M.} and Rodrigo Gularte-M{\'e}rida and Zhen Sun and Sho Fujisawa and Smith, {Caitlin G.} and Lorenzo Ferrando and {Martins Sebasti{\~a}o}, {Ana Paula} and Yonina Bykov and Anqi Li and Catarina Silveira and Ashley, {Charles W.} and Anthe Stylianou and Pier Selenica and Samore, {Wesley R.} and Jungbluth, {Achim A.} and Dmitriy Zamarin and Abu-Rustum, {Nadeem R.} and Kristian Helin and Soslow, {Robert A.} and Reis-Filho, {Jorge S.} and Esther Oliva and Britta Weigelt",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

day = "1",

doi = "10.1038/s41467-019-13806-x",

language = "English",

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Kim, SH, Da Cruz Paula, A, Basili, T, Dopeso, H, Bi, R, Pareja, F, da Silva, EM, Gularte-Mérida, R, Sun, Z, Fujisawa, S, Smith, CG, Ferrando, L, Martins Sebastião, AP, Bykov, Y, Li, A, Silveira, C, Ashley, CW, Stylianou, A, Selenica, P, Samore, WR, Jungbluth, AA, Zamarin, D, Abu-Rustum, NR, Helin, K, Soslow, RA, Reis-Filho, JS, Oliva, E & Weigelt, B 2020, 'Identification of recurrent FHL2-GLI2 oncogenic fusion in sclerosing stromal tumors of the ovary', Nature Communications, vol. 11, no. 1, 44. https://doi.org/10.1038/s41467-019-13806-x

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T1 - Identification of recurrent FHL2-GLI2 oncogenic fusion in sclerosing stromal tumors of the ovary

AU - Kim, Sarah H.

AU - Da Cruz Paula, Arnaud

AU - Basili, Thais

AU - Dopeso, Higinio

AU - Bi, Rui

AU - Pareja, Fresia

AU - da Silva, Edaise M.

AU - Gularte-Mérida, Rodrigo

AU - Sun, Zhen

AU - Fujisawa, Sho

AU - Smith, Caitlin G.

AU - Ferrando, Lorenzo

AU - Martins Sebastião, Ana Paula

AU - Bykov, Yonina

AU - Li, Anqi

AU - Silveira, Catarina

AU - Ashley, Charles W.

AU - Stylianou, Anthe

AU - Selenica, Pier

AU - Samore, Wesley R.

AU - Jungbluth, Achim A.

AU - Zamarin, Dmitriy

AU - Abu-Rustum, Nadeem R.

AU - Helin, Kristian

AU - Soslow, Robert A.

AU - Reis-Filho, Jorge S.

AU - Oliva, Esther

AU - Weigelt, Britta

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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.

AB - 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.

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DO - 10.1038/s41467-019-13806-x

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VL - 11

JO - Nature Communications

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ER -

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

Abstract

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