Molecular profiling of long-term IDH-wildtype glioblastoma survivors

Danielle M. Burgenske, Jie Yang, Paul A. Decker, Thomas M. Kollmeyer, Matthew L. Kosel, Ann C. Mladek, Alissa A. Caron, Rachael A. Vaubel, Shiv K. Gupta, Gaspar J. Kitange, Hugues Sicotte, Ryan S. Youland, Dioval Remonde, Jesse S. Voss, Emily G.Barr Fritcher, Kathryn L. Kolsky, Cristiane M. Ida, Fredric Meyer, Daniel H. Lachance, Ian J. ParneyBenjamin R. Kipp, Caterina Giannini, Erik P. Sulman, Robert B. Jenkins, Jeanette E. Eckel-Passow, Jann N. Sarkaria

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Background: Glioblastoma (GBM) represents an aggressive cancer type with a median survival of only 14 months. With fewer than 5% of patients surviving 5 years, comprehensive profiling of these rare patients could elucidate prognostic biomarkers that may confer better patient outcomes. We utilized multiple molecular approaches to characterize the largest patient cohort of isocitrate dehydrogenase (IDH)-wildtype GBM long-term survivors (LTS) to date. Methods: Retrospective analysis was performed on 49 archived formalin-fixed paraffin embedded tumor specimens from patients diagnosed with GBM at the Mayo Clinic between December 1995 and September 2013. These patient samples were subdivided into 2 groups based on survival (12 LTS, 37 short-term survivors [STS]) and subsequently examined by mutation sequencing, copy number analysis, methylation profiling, and gene expression. Results: Of the 49 patients analyzed in this study, LTS were younger at diagnosis (P = 0.016), more likely to be female (P = 0.048), and MGMT promoter methylated (UniD, P = 0.01). IDH-wildtype STS and LTS demonstrated classic GBM mutations and copy number changes. Pathway analysis of differentially expressed genes showed LTS enrichment for sphingomyelin metabolism, which has been linked to decreased GBM growth, invasion, and angiogenesis. STS were enriched for DNA repair and cell cycle control networks. Conclusions: While our findings largely report remarkable similarity between these LTS and more typical STS, unique attributes were observed in regard to altered gene expression and pathway enrichment. These attributes may be valuable prognostic markers and are worth further examination. Importantly, this study also underscores the limitations of existing biomarkers and classification methods in predicting patient prognosis.

Original languageEnglish (US)
Pages (from-to)1458-1469
Number of pages12
JournalNeuro-oncology
Volume21
Issue number11
DOIs
StatePublished - Nov 4 2019

Keywords

  • copy number alterations
  • glioblastoma
  • methylation
  • mutation analysis
  • RNA sequencing

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

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    Burgenske, D. M., Yang, J., Decker, P. A., Kollmeyer, T. M., Kosel, M. L., Mladek, A. C., Caron, A. A., Vaubel, R. A., Gupta, S. K., Kitange, G. J., Sicotte, H., Youland, R. S., Remonde, D., Voss, J. S., Fritcher, E. G. B., Kolsky, K. L., Ida, C. M., Meyer, F., Lachance, D. H., ... Sarkaria, J. N. (2019). Molecular profiling of long-term IDH-wildtype glioblastoma survivors. Neuro-oncology, 21(11), 1458-1469. https://doi.org/10.1093/neuonc/noz129