Cross-Species Genomics Reveals Oncogenic Dependencies in ZFTA/C11orf95 Fusion-Positive Supratentorial Ependymomas
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Cross-Species Genomics Reveals Oncogenic Dependencies in ZFTA/C11orf95 Fusion-Positive Supratentorial Ependymomas. / Zheng, Tuyu; Ghasemi, David R; Okonechnikov, Konstantin; Korshunov, Andrey; Sill, Martin; Maass, Kendra K; Benites Goncalves da Silva, Patricia; Ryzhova, Marina; Gojo, Johannes; Stichel, Damian; Arabzade, Amir; Kupp, Robert; Benzel, Julia; Taya, Shinichiro; Adachi, Toma; Shiraishi, Ryo; Gerber, Nicolas U; Sturm, Dominik; Ecker, Jonas; Sievers, Philipp; Selt, Florian; Chapman, Rebecca; Haberler, Christine; Figarella-Branger, Dominique; Reifenberger, Guido; Fleischhack, Gudrun; Rutkowski, Stefan; Donson, Andrew M; Ramaswamy, Vijay; Capper, David; Ellison, David W; Herold-Mende, Christel C; Schüller, Ulrich; Brandner, Sebastian; Driever, Pablo Hernáiz; Kros, Johan M; Snuderl, Matija; Milde, Till; Grundy, Richard G; Hoshino, Mikio; Mack, Stephen C; Gilbertson, Richard J; Jones, David T W; Kool, Marcel; von Deimling, Andreas; Pfister, Stefan M; Sahm, Felix; Kawauchi, Daisuke; Pajtler, Kristian W.
in: CANCER DISCOV, Jahrgang 11, Nr. 9, 09.2021, S. 2230-2247.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Cross-Species Genomics Reveals Oncogenic Dependencies in ZFTA/C11orf95 Fusion-Positive Supratentorial Ependymomas
AU - Zheng, Tuyu
AU - Ghasemi, David R
AU - Okonechnikov, Konstantin
AU - Korshunov, Andrey
AU - Sill, Martin
AU - Maass, Kendra K
AU - Benites Goncalves da Silva, Patricia
AU - Ryzhova, Marina
AU - Gojo, Johannes
AU - Stichel, Damian
AU - Arabzade, Amir
AU - Kupp, Robert
AU - Benzel, Julia
AU - Taya, Shinichiro
AU - Adachi, Toma
AU - Shiraishi, Ryo
AU - Gerber, Nicolas U
AU - Sturm, Dominik
AU - Ecker, Jonas
AU - Sievers, Philipp
AU - Selt, Florian
AU - Chapman, Rebecca
AU - Haberler, Christine
AU - Figarella-Branger, Dominique
AU - Reifenberger, Guido
AU - Fleischhack, Gudrun
AU - Rutkowski, Stefan
AU - Donson, Andrew M
AU - Ramaswamy, Vijay
AU - Capper, David
AU - Ellison, David W
AU - Herold-Mende, Christel C
AU - Schüller, Ulrich
AU - Brandner, Sebastian
AU - Driever, Pablo Hernáiz
AU - Kros, Johan M
AU - Snuderl, Matija
AU - Milde, Till
AU - Grundy, Richard G
AU - Hoshino, Mikio
AU - Mack, Stephen C
AU - Gilbertson, Richard J
AU - Jones, David T W
AU - Kool, Marcel
AU - von Deimling, Andreas
AU - Pfister, Stefan M
AU - Sahm, Felix
AU - Kawauchi, Daisuke
AU - Pajtler, Kristian W
N1 - ©2021 American Association for Cancer Research.
PY - 2021/9
Y1 - 2021/9
N2 - Molecular groups of supratentorial ependymomas comprise tumors with ZFTA-RELA or YAP1-involving fusions and fusion-negative subependymoma. However, occasionally supratentorial ependymomas cannot be readily assigned to any of these groups due to lack of detection of a typical fusion and/or ambiguous DNA methylation-based classification. An unbiased approach with a cohort of unprecedented size revealed distinct methylation clusters composed of tumors with ependymal but also various other histologic features containing alternative translocations that shared ZFTA as a partner gene. Somatic overexpression of ZFTA-associated fusion genes in the developing cerebral cortex is capable of inducing tumor formation in vivo, and cross-species comparative analyses identified GLI2 as a key downstream regulator of tumorigenesis in all tumors. Targeting GLI2 with arsenic trioxide caused extended survival of tumor-bearing animals, indicating a potential therapeutic vulnerability in ZFTA fusion-positive tumors. SIGNIFICANCE: ZFTA-RELA fusions are a hallmark feature of supratentorial ependymoma. We find that ZFTA acts as a partner for alternative transcriptional activators in oncogenic fusions of supratentorial tumors with various histologic characteristics. Establishing representative mouse models, we identify potential therapeutic targets shared by ZFTA fusion-positive tumors, such as GLI2.This article is highlighted in the In This Issue feature, p. 2113.
AB - Molecular groups of supratentorial ependymomas comprise tumors with ZFTA-RELA or YAP1-involving fusions and fusion-negative subependymoma. However, occasionally supratentorial ependymomas cannot be readily assigned to any of these groups due to lack of detection of a typical fusion and/or ambiguous DNA methylation-based classification. An unbiased approach with a cohort of unprecedented size revealed distinct methylation clusters composed of tumors with ependymal but also various other histologic features containing alternative translocations that shared ZFTA as a partner gene. Somatic overexpression of ZFTA-associated fusion genes in the developing cerebral cortex is capable of inducing tumor formation in vivo, and cross-species comparative analyses identified GLI2 as a key downstream regulator of tumorigenesis in all tumors. Targeting GLI2 with arsenic trioxide caused extended survival of tumor-bearing animals, indicating a potential therapeutic vulnerability in ZFTA fusion-positive tumors. SIGNIFICANCE: ZFTA-RELA fusions are a hallmark feature of supratentorial ependymoma. We find that ZFTA acts as a partner for alternative transcriptional activators in oncogenic fusions of supratentorial tumors with various histologic characteristics. Establishing representative mouse models, we identify potential therapeutic targets shared by ZFTA fusion-positive tumors, such as GLI2.This article is highlighted in the In This Issue feature, p. 2113.
U2 - 10.1158/2159-8290.CD-20-0963
DO - 10.1158/2159-8290.CD-20-0963
M3 - SCORING: Journal article
C2 - 33879448
VL - 11
SP - 2230
EP - 2247
JO - CANCER DISCOV
JF - CANCER DISCOV
SN - 2159-8274
IS - 9
ER -
