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Molecular genetic profiling reveals novel association between FLT3 mutation and survival in glioma

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Abstract

Introduction

Recent molecular characterization of gliomas has uncovered somatic gene variation and DNA methylation changes that are associated with etiology, prognosis, and therapeutic response. Here we describe genomic profiling of gliomas assessed for associations between genetic mutations and patient outcomes, including overall survival (OS) and recurrence-free survival (RFS).

Methods

Mutations in a 50-gene cancer panel, 1p19q co-deletion, and MGMT promoter methylation (MGMT methylation) status were obtained from tumor tissue of 293 glioma patients. Multivariable regression models for overall survival (OS) and recurrence-free survival (RFS) were constructed for MGMT methylation, 1p19q co-deletion, and gene mutations controlling for age, treatment status, and WHO grade.

Results

Mutational profiles of gliomas significantly differed based on WHO Grade, such as high prevalence of BRAF V600E, IDH1, and PTEN mutations in WHO Grade I, II/III, and IV tumors, respectively. In multivariate regression analysis, MGMT methylation and IDH1 mutations were significantly associated with improved OS (HR = 0.44, p = 0.0004 and HR = 0.21, p = 0.007, respectively), while FLT3 and TP53 mutations were significantly associated with poorer OS (HR = 19.46, p < 0.0001 and HR = 1.67, p = 0.014, respectively). MGMT methylation and IDH1 mutations were the only significant alterations associated with improved RFS in the model (HR = 0.42, p < 0.0001 and HR = 0.37, p = 0.002, respectively). These factors were then included in a combined model, which significantly exceeded the predictive value of the base model alone (age, surgery, radiation, chemo, grade) (likelihood ratio test OS p = 1.64 × 10–8 and RFS p = 3.80 × 10–7).

Conclusions

This study highlights the genomic landscape of gliomas in a single-institution cohort and identifies a novel association between FLT3 mutation and OS in gliomas.

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Authors and Affiliations

  1. Geisel School of Medicine At Dartmouth, Hanover, NH, Germany

    Kevin Shee, Meagan Chambers, Sophie J. Deharvengt, Joel A. Lefferts, Angeline S. Andrew, William F. Hickey & Gregory J. Tsongalis

  2. Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center, 03756, Lebanon, NH, Germany

    Edward G. Hughes, Sophie J. Deharvengt, Donald Green, Joel A. Lefferts, William F. Hickey & Gregory J. Tsongalis

  3. Department of Neurology, Dartmouth-Hitchcock Medical Center, Lebanon, NH, Germany

    Angeline S. Andrew

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  1. Kevin Shee
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Correspondence to Kevin Shee or Gregory J. Tsongalis.

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Shee, K., Chambers, M., Hughes, E.G. et al. Molecular genetic profiling reveals novel association between FLT3 mutation and survival in glioma. J Neurooncol 148, 473–480 (2020). https://doi.org/10.1007/s11060-020-03567-9

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