Genetic landscape of extreme responders with anaplastic oligodendroglioma.

Matthias Holdhoff,Jean-Paul Bahary,Thomas M Kollmeyer,Luis Souhami,Nickolas Papadopoulos,Srinivasan Yegnasubramanian,Arnab Chakravarti,Kenneth Kinzler,Peixin Zhang,Robert B Jenkins,Chetan Bettegowda,Ming Zhang,Young Kwok,Alan C Hartford,Gregory J Cairncross,Bert Vogelstein,Maria Werner-Wasik,Minesh P Mehta

doi:10.18632/oncotarget.16773

Abstract

BackgroundThe NRG Oncology RTOG 9402 trial showed significant survival benefit in patients with 1p/19q co-deleted anaplastic oligodendrogliomas (AO) who received both radiation (RT) and chemotherapy (PCV regimen) versus RT alone. Substantial separation of the survival curves was only seen after 7.3 years. We aimed to determine whether there are specific genetic alterations that distinguish co-deleted AO patients who benefit from the addition of PCV from those who do not. Methods: We performed whole exome sequencing on matched tumor and normal DNA from all available short-term (STS) and long-term survivors (LTS) who received RT+PCV. hTERT status and rs55705857 genotypes (G-allele) were analyzed in both cohorts. Results: Six STS (survival of <7.3y) and 7 LTS (survival of ≥7.3y and no progression) had sufficient material for analysis. There was no significant difference between the groups regarding age, performance status and extent of resection. On average, STS had 7 and LTS 4 mutations. Most common mutations in STS vs. LTS were: IDH1 (67 vs. 86%), CIC (50 vs. 71%) and FUBP1 (17 vs. 71%). The hTERT promoter was mutated in 83% STS and 86% LTS. Genotyping of rs55705857 showed a higher prevalence of G allele carriers in LTS than STS (43 vs. 17%).ConclusionsThese findings confirm that IDH, CIC, FUBP1 mutations and rs55705857 genotype are common in AO. No distinct genetic signature was identified to differentiate STS and LTS.

Highlights

Oligodendrogliomas are the second most common adult primary brain tumor, constituting about 20% of all glial tumors
Our aim was to determine the genetic landscape of extreme responders in NRG Oncology Radiation Therapy Oncology Group (RTOG) 9402 and to identify alterations that could be predictive of benefit from PCV
“Long-term survivors” were patients who had never progressed based on available follow-up data

Summary

Introduction

Oligodendrogliomas are the second most common adult primary brain tumor, constituting about 20% of all glial tumors. In addition to 1p/19q co-deletion, it has become well recognized that mutations in IDH1/2 are present in the vast majority of oligodendrogliomas [5, 6]. Mutations in the TERT promoter are present in ~80% of oligodendrogliomas and are mutually exclusive of ATRX mutations commonly seen in nonoligodendroglial lower grade gliomas [6, 9]. 1p/19q co-deletion, IDH1/2 and TERT promoter mutation are oligodendroglioma defining alterations [10, 11]. The NRG Oncology RTOG 9402 trial showed significant survival benefit in patients with 1p/19q co-deleted anaplastic oligodendrogliomas (AO) who received both radiation (RT) and chemotherapy (PCV regimen) versus RT alone. Most common mutations in STS vs LTS were: IDH1 (67 vs 86%), CIC (50 vs 71%) and FUBP1 (17 vs 71%). The hTERT promoter was mutated in 83% STS and 86% LTS. Genotyping of rs55705857 showed a higher prevalence of G allele carriers in LTS than STS (43 vs. 17%)

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