TY - JOUR
T1 - Multiplatform profiling of meningioma provides molecular insight and prioritization of drug targets for rational clinical trial design
AU - Everson, Richard G.
AU - Hashimoto, Yuuri
AU - Freeman, Jacob L.
AU - Hodges, Tiffany R.
AU - Huse, Jason
AU - Zhou, Shouhao
AU - Xiu, Joanne
AU - Spetzler, David
AU - Sanai, Nader
AU - Kim, Lyndon
AU - Kesari, Santosh
AU - Brenner, Andrew
AU - De Monte, Franco
AU - Heimberger, Amy
AU - Raza, Shaan M.
N1 - Publisher Copyright:
© 2018, Springer Science+Business Media, LLC, part of Springer Nature.
PY - 2018/9/1
Y1 - 2018/9/1
N2 - Introduction: Surgery and radiation therapy are the standard treatment options for meningiomas, but these treatments are not always feasible. Expression profiling was performed to determine the presence of therapeutic actionable biomarkers for prioritization and selection of agents. Methods: Meningiomas (n = 115) were profiled using a variety of strategies including next-generation sequencing (592-gene panel: n = 14; 47-gene panel: n = 94), immunohistochemistry (n = 8–110), and fluorescent and chromogenic in situ hybridization (n = 5–70) to determine mutational and expression status. Results: The median age of patients in the cohort was 60 years, with a range spanning 6–90 years; 52% were female. The most frequently expressed protein markers were EGFR (93%; n = 44), followed by PTEN (77%; n = 110), BCRP (75%; n = 8), MRP1 (65%, n = 23), PGP (62%; n = 84), and MGMT (55%; n = 97). The most frequent mutation among all meningioma grades occurred in the NF2 gene at 85% (11/13). Recurring mutations in SMO and AKT1 were also occasionally detected. PD-L1 was expressed in 25% of grade III cases (2/8) but not in grade I or II tumors. PD-1 + T cells were present in 46% (24/52) of meningiomas. TOP2A and thymidylate synthase expression increased with grade (I = 5%, II = 22%, III = 62% and I = 5%, II = 23%, III = 47%, respectively), whereas progesterone receptor expression decreased with grade (I = 79%, II = 41%, III = 29%). Conclusion: If predicated on tumor expression, our data suggest that therapeutics directed toward NF2 and TOP2A could be considered for most meningioma patients.
AB - Introduction: Surgery and radiation therapy are the standard treatment options for meningiomas, but these treatments are not always feasible. Expression profiling was performed to determine the presence of therapeutic actionable biomarkers for prioritization and selection of agents. Methods: Meningiomas (n = 115) were profiled using a variety of strategies including next-generation sequencing (592-gene panel: n = 14; 47-gene panel: n = 94), immunohistochemistry (n = 8–110), and fluorescent and chromogenic in situ hybridization (n = 5–70) to determine mutational and expression status. Results: The median age of patients in the cohort was 60 years, with a range spanning 6–90 years; 52% were female. The most frequently expressed protein markers were EGFR (93%; n = 44), followed by PTEN (77%; n = 110), BCRP (75%; n = 8), MRP1 (65%, n = 23), PGP (62%; n = 84), and MGMT (55%; n = 97). The most frequent mutation among all meningioma grades occurred in the NF2 gene at 85% (11/13). Recurring mutations in SMO and AKT1 were also occasionally detected. PD-L1 was expressed in 25% of grade III cases (2/8) but not in grade I or II tumors. PD-1 + T cells were present in 46% (24/52) of meningiomas. TOP2A and thymidylate synthase expression increased with grade (I = 5%, II = 22%, III = 62% and I = 5%, II = 23%, III = 47%, respectively), whereas progesterone receptor expression decreased with grade (I = 79%, II = 41%, III = 29%). Conclusion: If predicated on tumor expression, our data suggest that therapeutics directed toward NF2 and TOP2A could be considered for most meningioma patients.
KW - Meningioma
KW - Molecular profiling
KW - NF2
KW - NGS
KW - PD-1
KW - TOP2A
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U2 - 10.1007/s11060-018-2891-8
DO - 10.1007/s11060-018-2891-8
M3 - Article
C2 - 29846894
AN - SCOPUS:85047822404
SN - 0167-594X
VL - 139
SP - 469
EP - 478
JO - Journal of Neuro-Oncology
JF - Journal of Neuro-Oncology
IS - 2
ER -