TY - JOUR
T1 - Phosphoproteomic and Kinomic Signature of Clinically Aggressive Grade I (1.5) Meningiomas Reveals RB1 Signaling as a Novel Mediator and Biomarker
AU - Parada, Carolina A.
AU - Osbun, Joshua W.
AU - Busald, Tina
AU - Karasozen, Yigit
AU - Kaur, Sumanpreet
AU - Shi, Min
AU - Barber, Jason
AU - Adidharma, Widya
AU - Cimino, Patrick J.
AU - Pan, Catherine
AU - Gonzalez-Cuyar, Luis F.
AU - Rostomily, Robert
AU - Born, Donald E.
AU - Zhang, Jing
AU - Ferreira, Manuel
N1 - Funding Information:
This study was supported by University of Washington Department of Neurosurgery, Goertzen Foundation, and Kapogiannatos family funds (to M. Ferreira). The funding sources had no role in the design and conduct of the study, collection, management, analysis and interpretation of the data, preparation, review or approval of the manuscript, or decision to submit the manuscript for publication.
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2020/1/1
Y1 - 2020/1/1
N2 - Purpose: Most World Health Organization (WHO) grade I meningiomas carry a favorable prognosis. Some become clinically aggressive with recurrence, invasion, and resistance to conventional therapies (grade 1.5; recurrent/progressive WHO grade I tumors requiring further treatment within 10 years). We aimed to identify biomarker signatures in grade 1.5 meningiomas where histopathology and genetic evaluation has fallen short. Experimental Design: Mass spectrometry (MS)–based phosphoproteomics and peptide chip array kinomics were used to compare grade I and 1.5 tumors. Ingenuity Pathway Analysis (IPA) identified alterations in signaling pathways with validation by Western blot analysis. The selected biomarker was evaluated in an independent cohort of 140 samples (79/140 genotyped for meningioma mutations) by tissue microarray and correlated with clinical variables. Results: The MS-based phosphoproteomics revealed differential Ser/Thr phosphorylation in 32 phosphopeptides. The kinomic profiling by peptide chip array identified 10 phosphopeptides, including a 360% increase in phosphorylation of RB1, in the 1.5 group. IPA of the combined datasets and Western blot validation revealed regulation of AKT and cell-cycle checkpoint cascades. RB1 hyperphosphorylation at the S780 site distinguished grade 1.5 meningiomas in an independent cohort of 140 samples and was associated with decreased progression/ recurrence-free survival. Mutations in NF2, TRAF7, SMO, KLF4, and AKT1 E17K did not predict RB1 S780 staining or progression in grade 1.5 meningiomas. Conclusions: RB1 S780 staining distinguishes grade 1.5 meningiomas, independent of histology, subtype, WHO grade, or genotype. This promising biomarker for risk stratification of histologically bland WHO grade I meningiomas provides insight into the pathways of oncogenesis driving these outlying clinically aggressive tumors.
AB - Purpose: Most World Health Organization (WHO) grade I meningiomas carry a favorable prognosis. Some become clinically aggressive with recurrence, invasion, and resistance to conventional therapies (grade 1.5; recurrent/progressive WHO grade I tumors requiring further treatment within 10 years). We aimed to identify biomarker signatures in grade 1.5 meningiomas where histopathology and genetic evaluation has fallen short. Experimental Design: Mass spectrometry (MS)–based phosphoproteomics and peptide chip array kinomics were used to compare grade I and 1.5 tumors. Ingenuity Pathway Analysis (IPA) identified alterations in signaling pathways with validation by Western blot analysis. The selected biomarker was evaluated in an independent cohort of 140 samples (79/140 genotyped for meningioma mutations) by tissue microarray and correlated with clinical variables. Results: The MS-based phosphoproteomics revealed differential Ser/Thr phosphorylation in 32 phosphopeptides. The kinomic profiling by peptide chip array identified 10 phosphopeptides, including a 360% increase in phosphorylation of RB1, in the 1.5 group. IPA of the combined datasets and Western blot validation revealed regulation of AKT and cell-cycle checkpoint cascades. RB1 hyperphosphorylation at the S780 site distinguished grade 1.5 meningiomas in an independent cohort of 140 samples and was associated with decreased progression/ recurrence-free survival. Mutations in NF2, TRAF7, SMO, KLF4, and AKT1 E17K did not predict RB1 S780 staining or progression in grade 1.5 meningiomas. Conclusions: RB1 S780 staining distinguishes grade 1.5 meningiomas, independent of histology, subtype, WHO grade, or genotype. This promising biomarker for risk stratification of histologically bland WHO grade I meningiomas provides insight into the pathways of oncogenesis driving these outlying clinically aggressive tumors.
KW - Biomarkers, Tumor/metabolism
KW - Disease Progression
KW - Follow-Up Studies
KW - Humans
KW - Mass Spectrometry/methods
KW - Meningeal Neoplasms/metabolism
KW - Meningioma/metabolism
KW - Neoplasm Grading
KW - Neoplasm Recurrence, Local/metabolism
KW - Phosphoproteins/metabolism
KW - Prognosis
KW - Protein Kinases/metabolism
KW - Proteome/analysis
KW - Retinoblastoma Binding Proteins/metabolism
KW - Risk Factors
KW - Signal Transduction
KW - Tissue Array Analysis/methods
KW - Ubiquitin-Protein Ligases/metabolism
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U2 - 10.1158/1078-0432.CCR-18-0641
DO - 10.1158/1078-0432.CCR-18-0641
M3 - Article
C2 - 31615938
AN - SCOPUS:85077476630
SN - 1078-0432
VL - 26
SP - 193
EP - 205
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 1
ER -