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. 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 () and Britta Weigelt ()
Additional contact information
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
Fresia Pareja: Memorial Sloan Kettering Cancer Center
Edaise M. Silva: Memorial Sloan Kettering Cancer Center
Rodrigo Gularte-Mérida: 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
Ana Paula Martins Sebastião: Memorial Sloan Kettering Cancer Center
Yonina Bykov: Memorial Sloan Kettering Cancer Center
Anqi Li: Memorial Sloan Kettering Cancer Center
Catarina Silveira: Memorial Sloan Kettering Cancer Center
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
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

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-019-13806-x

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