Identification of recurrent FHL2-GLI2 oncogenic fusion in sclerosing stromal tumors of the ovary
Authors: Pier Selenica
Kristian Helin
Britta Weigelt
Charles W Ashley
Dmitriy Zamarin
Yonina Bykov
Edaise M da Silva
Zhen Sun
Sarah H Kim
Lorenzo Ferrando
Nadeem R Abu-Rustum
Esther Oliva
Anqi Li
Thais Basili
Sho Fujisawa
Wesley R Samore
Arnaud Da Cruz Paula
Caitlin G Smith
Rui Bi
Anthe Stylianou
Achim A Jungbluth
Higinio Dopeso
Catarina Silveira
Fresia Pareja
Robert A Soslow
Ana Paula Martins Sebastião
Rodrigo Gularte-Mérida
Jorge S Reis-Filho
Journal: Nature Communications (2020)
Discipline: Multidisciplinary
Keywords: Sclerosing stromal tumor; FHL2-GLI2 fusion genes; Sonic Hedgehog pathway; sex cord-stromal tumor; ovarian neoplasms
Affiliations: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA., Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA., Department of Pathology, Fudan University Shanghai Cancer Center, 200032, Shanghai, People's Republic of China., Cell Biology Program and Center for Epigenetics, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA., Molecular Cytology Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA., Department of Internal Medicine, University of Genoa, 16126, Genova, Italy., Department of Medical Pathology, Federal University of Paraná, Curitiba, Paraná, 80060-000, Brazil., Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA., GenoMed SA, Institute of Molecular Medicine, University of Lisbon, 1649, Lisbon, Portugal., Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA., Biotech Research and Innovation Centre (BRIC), University of Copenhagen, 2200, Copenhagen, Denmark., The Novo Nordisk Foundation for Stem Cell Biology (Danstem), University of Copenhagen, 2200, Copenhagen, Denmark., Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA. ., Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. .

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. 

Retracted: No

PubPeer comments:
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