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

被引：37

作者：

Kim, Sarah H. ^{[1
]}

Paula, Arnaud Da Cruz ^{[1
]}

Basili, Thais ^{[2
]}

Dopeso, Higinio ^{[2
]}

Bi, Rui ^{[2
,3
]}

Pareja, Fresia ^{[2
]}

da Silva, Edaise M. ^{[2
]}

Gularte-Merida, Rodrigo ^{[1
,2
]}

Sun, Zhen ^{[4
,5
]}

Fujisawa, Sho ^{[6
]}

Smith, Caitlin G. ^{[2
]}

Ferrando, Lorenzo ^{[2
,7
]}

Martins Sebastiao, Ana Paula ^{[2
,8
]}

Bykov, Yonina ^{[9
]}

Li, Anqi ^{[2
,3
]}

Silveira, Catarina ^{[2
,10
]}

Ashley, Charles W. ^{[1
]}

Stylianou, Anthe ^{[1
]}

Selenica, Pier ^{[2
]}

Samore, Wesley R. ^{[11
]}

Jungbluth, Achim A. ^{[2
]}

Zamarin, Dmitriy ^{[9
]}

Abu-Rustum, Nadeem R. ^{[1
]}

Helin, Kristian ^{[4
,5
,12
,13
]}

Soslow, Robert A. ^{[2
]}

Reis-Filho, Jorge S. ^{[2
]}

Oliva, Esther ^{[11
]}

Weigelt, Britta ^{[2
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10065 USA

[2] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA

[3] Fudan Univ, Dept Pathol, Shanghai Canc Ctr, Shanghai 200032, Peoples R China

[4] Mem Sloan Kettering Canc Ctr, Cell Biol Program, New York, NY 10065 USA

[5] Mem Sloan Kettering Canc Ctr, Ctr Epigenet, New York, NY 10065 USA

[6] Mem Sloan Kettering Canc Ctr, Mol Cytol Core Facil, New York, NY 10065 USA

[7] Univ Genoa, Dept Internal Med, I-16126 Genoa, Italy

[8] Univ Fed Parana, Dept Med Pathol, BR-80060000 Curitiba, Parana, Brazil

[9] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA

[10] Univ Lisbon, Inst Mol Med, GenoMed SA, P-1649 Lisbon, Portugal

[11] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA

[12] Univ Copenhagen, Biotech Res & Innovat Ctr BRIC, DK-2200 Copenhagen, Denmark

[13] Univ Copenhagen, Novo Nordisk Fdn Stem Cell Biol Danstem, DK-2200 Copenhagen, Denmark

来源：

NATURE COMMUNICATIONS | 2020年 / 11卷 / 01期

基金：

美国国家卫生研究院;

关键词：

DIFFERENTIAL EXPRESSION ANALYSIS; TRANSCRIPTIONAL ACTIVITY; GENE-EXPRESSION; CELL TUMORS; CARCINOMAS; MUTATIONS; HEDGEHOG; BREAST; DISCOVERY; TARGET;

D O I：

10.1038/s41467-019-13806-x

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：16

共 71 条

[1] FOXL2 Is a Sensitive and Specific Marker for Sex Cord-Stromal Tumors of the Ovary [J].

Al-Agha, Osama M. ;

Huwait, Hassan F. ;

Chow, Christine ;

Yang, Winnie ;

Senz, Janine ;

Kalloger, Steve E. ;

Huntsman, David G. ;

Young, Robert H. ;

Gilks, C. Blake .

AMERICAN JOURNAL OF SURGICAL PATHOLOGY, 2011, 35 (04) :484-494

[2] Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1 [J].

Barbie, David A. ;

Tamayo, Pablo ;

Boehm, Jesse S. ;

Kim, So Young ;

Moody, Susan E. ;

Dunn, Ian F. ;

Schinzel, Anna C. ;

Sandy, Peter ;

Meylan, Etienne ;

Scholl, Claudia ;

Froehling, Stefan ;

Chan, Edmond M. ;

Sos, Martin L. ;

Michel, Kathrin ;

Mermel, Craig ;

Silver, Serena J. ;

Weir, Barbara A. ;

Reiling, Jan H. ;

Sheng, Qing ;

Gupta, Piyush B. ;

Wadlow, Raymond C. ;

Le, Hanh ;

Hoersch, Sebastian ;

Wittner, Ben S. ;

Ramaswamy, Sridhar ;

Livingston, David M. ;

Sabatini, David M. ;

Meyerson, Matthew ;

Thomas, Roman K. ;

Lander, Eric S. ;

Mesirov, Jill P. ;

Root, David E. ;

Gilliland, D. Gary ;

Jacks, Tyler ;

Hahn, William C. .

NATURE, 2009, 462 (7269) :108-U122

[3] Sclerosing epithelioid mesenchymal neoplasm of the pancreas - a proposed new entity [J].

Basturk, Olca ;

Weigelt, Britta ;

Adsay, Volkan ;

Benhamida, Jamal K. ;

Askan, Gokce ;

Wang, Lu ;

Arcila, Maria E. ;

Zamboni, Giuseppe ;

Fukushima, Noriyoshi ;

Gularte-Merida, Rodrigo ;

Paula, Arnaud Da Cruz ;

Selenica, Pier ;

Kumar, Rahul ;

Pareja, Fresia ;

Maher, Christopher A. ;

Scholes, John ;

Oda, Yoshinao ;

Santini, Donatella ;

Doyle, Leona A. ;

Petersen, Iver ;

Flucke, Uta ;

Koelsche, Christian ;

Reynolds, Samuel J. ;

Yavas, Aslihan ;

von Deimling, Andreas ;

Reis-Filho, Jorge S. ;

Klimstra, David S. .

MODERN PATHOLOGY, 2020, 33 (03) :456-467

[4] Integrated genomic analyses of ovarian carcinoma [J].

Bell, D. ;

Berchuck, A. ;

Birrer, M. ;

Chien, J. ;

Cramer, D. W. ;

Dao, F. ;

Dhir, R. ;

DiSaia, P. ;

Gabra, H. ;

Glenn, P. ;

Godwin, A. K. ;

Gross, J. ;

Hartmann, L. ;

Huang, M. ;

Huntsman, D. G. ;

Iacocca, M. ;

Imielinski, M. ;

Kalloger, S. ;

Karlan, B. Y. ;

Levine, D. A. ;

Mills, G. B. ;

Morrison, C. ;

Mutch, D. ;

Olvera, N. ;

Orsulic, S. ;

Park, K. ;

Petrelli, N. ;

Rabeno, B. ;

Rader, J. S. ;

Sikic, B. I. ;

Smith-McCune, K. ;

Sood, A. K. ;

Bowtell, D. ;

Penny, R. ;

Testa, J. R. ;

Chang, K. ;

Dinh, H. H. ;

Drummond, J. A. ;

Fowler, G. ;

Gunaratne, P. ;

Hawes, A. C. ;

Kovar, C. L. ;

Lewis, L. R. ;

Morgan, M. B. ;

Newsham, I. F. ;

Santibanez, J. ;

Reid, J. G. ;

Trevino, L. R. ;

Wu, Y. -Q. ;

Wang, M. .

NATURE, 2011, 474 (7353) :609-615

[5] Controlling the false discovery rate in behavior genetics research [J].

Benjamini, Y ;

Drai, D ;

Elmer, G ;

Kafkafi, N ;

Golani, I .

BEHAVIOURAL BRAIN RESEARCH, 2001, 125 (1-2) :279-284

[6] Sclerosing Stromal Tumors With Prominent Luteinization During Pregnancy: A Report of 8 Cases Emphasizing Diagnostic Problems [J].

Bennett, Jennifer A. ;

Oliva, Esther ;

Young, Robert H. .

INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY, 2015, 34 (04) :357-362

[7] FHL2 promotes tubular epithelial-to-mesenchymal transition through modulating β-catenin signalling [J].

Cai, Ting ;

Sun, Danqin ;

Duan, Ying ;

Qiu, Yumei ;

Dai, Chunsun ;

Yang, Junwei ;

He, Weichun .

JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, 2018, 22 (03) :1684-1695

[8] Expression of calretinin in human ovary, testis, and ovarian sex cord-stromal tumors [J].

Cao, QJ ;

Jones, JG ;

Li, MM .

INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY, 2001, 20 (04) :346-352

[9] Absolute quantification of somatic DNA alterations in human cancer [J].

Carter, Scott L. ;

Cibulskis, Kristian ;

Helman, Elena ;

McKenna, Aaron ;

Shen, Hui ;

Zack, Travis ;

Laird, Peter W. ;

Onofrio, Robert C. ;

Winckler, Wendy ;

Weir, Barbara A. ;

Beroukhim, Rameen ;

Pellman, David ;

Levine, Douglas A. ;

Lander, Eric S. ;

Meyerson, Matthew ;

Getz, Gad .

NATURE BIOTECHNOLOGY, 2012, 30 (05) :413-+

[10]

CHALVARDJIAN A, 1973, CANCER-AM CANCER SOC, V31, P664, DOI 10.1002/1097-0142(197303)31:3<664::AID-CNCR2820310327>3.0.CO

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