Phosphoproteomic and Kinomic Signature of Clinically Aggressive Grade I (1.5) Meningiomas Reveals RB1 Signaling as a Novel Mediator and Biomarker

Clin Cancer Res. 2020 Jan 1;26(1):193-205. doi: 10.1158/1078-0432.CCR-18-0641. Epub 2019 Oct 15.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor / metabolism*
  • Disease Progression
  • Follow-Up Studies
  • Humans
  • Mass Spectrometry / methods
  • Meningeal Neoplasms / metabolism
  • Meningeal Neoplasms / pathology*
  • Meningioma / metabolism
  • Meningioma / pathology*
  • Neoplasm Grading
  • Neoplasm Recurrence, Local / metabolism
  • Neoplasm Recurrence, Local / pathology*
  • Phosphoproteins / metabolism*
  • Prognosis
  • Protein Kinases / metabolism*
  • Proteome / analysis
  • Proteome / metabolism
  • Retinoblastoma Binding Proteins / metabolism*
  • Risk Factors
  • Signal Transduction
  • Tissue Array Analysis / methods
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • Biomarkers, Tumor
  • Phosphoproteins
  • Proteome
  • RB1 protein, human
  • Retinoblastoma Binding Proteins
  • Ubiquitin-Protein Ligases
  • Protein Kinases