Dataset Information

Genetic landscape of extreme responders with anaplastic oligodendroglioma.

ABSTRACT: BACKGROUND: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. 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%). CONCLUSIONS:These 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.

SUBMITTER: Holdhoff M

PROVIDER: S-EPMC5482595 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Genetic landscape of extreme responders with anaplastic oligodendroglioma.

Holdhoff Matthias M Cairncross Gregory J GJ Kollmeyer Thomas M TM Zhang Ming M Zhang Peixin P Mehta Minesh P MP Werner-Wasik Maria M Souhami Luis L Bahary Jean-Paul JP Kwok Young Y Hartford Alan C AC Chakravarti Arnab A Yegnasubramanian Srinivasan S Vogelstein Bert B Papadopoulos Nickolas N Kinzler Kenneth K Jenkins Robert B RB Bettegowda Chetan C

Oncotarget 20170501 22

<h4>Background</h4>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. 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.<h4>Methods</h4> ...[more]

PMID: 28388591

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Project description:Pleomorphic xanthoastrocytoma (PXA) is an astrocytic neoplasm that is typically well circumscribed and can have a relatively favorable prognosis. Tumor progression to anaplastic PXA (WHO grade III), however, is associated with a more aggressive biologic behavior and worse prognosis. The factors that drive anaplastic progression are largely unknown. We performed comprehensive genomic profiling on a set of 23 PXAs from 19 patients, including 15 with anaplastic PXA. Four patients had tumor tissue from multiple recurrences, including two with anaplastic progression. We find that PXAs are genetically defined by the combination of CDKN2A biallelic inactivation and RAF alterations that were present in all 19 cases, most commonly as CDKN2A homozygous deletion and BRAF p.V600E mutation but also occasionally BRAF or RAF1 fusions or other rearrangements. The third most commonly altered gene in anaplastic PXA was TERT, with 47% (7/15) harboring TERT alterations, either gene amplification (n = 2) or promoter hotspot mutation (n = 5). In tumor pairs analyzed before and after anaplastic progression, two had increased copy number alterations and one had TERT promoter mutation at recurrence. Less commonly altered genes included TP53, BCOR, BCORL1, ARID1A, ATRX, PTEN, and BCL6. All PXA in this cohort were IDH and histone H3 wildtype, and did not contain alterations in EGFR. Genetic profiling performed on six regions from the same tumor identified intratumoral genomic heterogeneity, likely reflecting clonal evolution during tumor progression. Overall, anaplastic PXA is characterized by the combination of CDKN2A biallelic inactivation and oncogenic RAF kinase signaling as well as a relatively small number of additional genetic alterations, with the most common being TERT amplification or promoter mutation. These data define a distinct molecular profile for PXA and suggest additional genetic alterations, including TERT, may be associated with anaplastic progression.

Project description:Anaplastic oligodendroglioma is a rare disease with an inadequately understood prognosis. The aim of this study was to investigate factors associated with survival outcome in anaplastic oligodendroglioma patients. A population-based cohort study was conducted based on the Surveillance, Epidemiology, and End Results program. In total, 1899 patients with a histological diagnosis of anaplastic oligodendroglioma from 1973 to 2015 were included. Mean age at diagnosis was 49.2 years, and 56.19% were male. In our study, 62.40% of patients were married, and 87.05% were white. Most patients (90.42%) were diagnosed with anaplastic oligodendroglioma as their first malignant primary tumor, but 9.58% had a diagnosis of at least one other primary malignancy; 87.89% of patients had received cancer-directed surgery. Patients receiving surgery had a better prognosis for overall survival compared to those not receiving surgery after propensity score matching analysis (p<0.05). The overall 1-, 3-, 5-, and 10-year survival of anaplastic oligodendroglioma was 78.7%, 60%, 50.2%, and 36.2%, respectively. Kaplan-Meier analysis indicated that age, marital status, presence of multiple primary malignancies, and surgical treatment were associated with overall survival, whereas sex and race were not. Moreover, age at diagnosis of 52 years was calculated as an optimal cutoff value to distinguish better and worse overall survival. Multivariate Cox proportional hazard analysis indicated that older age (OR 1.040, 95%CI1.035-1.045), single patients (OR 1.293, 95%CI 1.103-1.515), and presence of multiple primary malignancies (OR 1.501, 95%CI 1.238-1.820) were significantly associated with worse overall survival, whereas surgery (OR 0.584, 95%CI 0.494-0.689) was associated with better overall survival. A nomogram predicting 5-, and 10-year survival probability for anaplastic oligodendroglioma was constructed based on these variables. In conclusion, age, marital status, presence of multiple primary malignancies, and surgical treatment were associated with survival of anaplastic oligodendroglioma.

Dataset Information

Genetic landscape of extreme responders with anaplastic oligodendroglioma.

Publications

Genetic landscape of extreme responders with anaplastic oligodendroglioma.

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