Phosphoproteomic and kinomic signature of clinically aggressive grade I (1.5) meningiomas reveals Rb1 signaling as a novel mediator and biomarker a C

Carolina A. Parada, Joshua W. Osbun, Tina Busald, Yigit Karasozen, Sumanpreet Kaur, Min Shi, Jason Barber, Widya Adidharma, Patrick J. Cimino, Catherine Pan, Luis F. Gonzalez-Cuyar, Robert Rostomily, Donald E. Born, Jing Zhang, Manuel Ferreira

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)193-205
Number of pages13
JournalClinical Cancer Research
Volume26
Issue number1
DOIs
StatePublished - Jan 1 2020

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    Parada, C. A., Osbun, J. W., Busald, T., Karasozen, Y., Kaur, S., Shi, M., Barber, J., Adidharma, W., Cimino, P. J., Pan, C., Gonzalez-Cuyar, L. F., Rostomily, R., Born, D. E., Zhang, J., & Ferreira, M. (2020). Phosphoproteomic and kinomic signature of clinically aggressive grade I (1.5) meningiomas reveals Rb1 signaling as a novel mediator and biomarker a C. Clinical Cancer Research, 26(1), 193-205. https://doi.org/10.1158/1078-0432.CCR-18-0641