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Not all 1p/19q non-codeleted oligodendroglial tumors are astrocytic.

ABSTRACT: Although 1p/19q codeletion is the genetic hallmark defining oligodendrogliomas, approximately 30-40% of oligodendroglial tumors have intact 1p/19q in the literature and they demonstrate a worse prognosis. This group of 1p/19q intact oligodendroglial tumors is frequently suggested to be astrocytic in nature with TP53 and ATRX mutations but actually remains under-investigated. In the present study, we provided evidence that not all 1p/19q intact oligodendroglial tumors are astrocytic through histologic and molecular approaches. We examined 1p/19q status by FISH in a large cohort of 337 oligodendroglial tumors and identified 39.8% lacking 1p/19q codeletion which was independently associated with poor prognosis. Among this 1p/19q intact oligodendroglial tumor cohort, 58 cases demonstrated classic oligodendroglial histology which showed older patient age, better prognosis, association with grade III histology, PDGFRA expression, TERTp mutation, as well as frequent IDH mutation. More than half of the 1p/19q intact oligodendroglial tumors showed lack of astrocytic defining markers, p53 expression and ATRX loss. TP53 mutational analysis was additionally conducted in 45 cases of the 1p/19q intact oligodendroglial tumors. Wild-type TP53 was detected in 71.1% of cases which was associated with classic oligodendroglial histology. Importantly, IDH and TERTp co-occurred in 75% of 1p/19q intact, TP53 wild-type oligodendrogliomas, highlighting the potential of the co-mutations in assisting diagnosis of oligodendrogliomas in tumors with clear cell morphology and non-codeleted 1p/19q status. In summary, our study demonstrated that not all 1p/19q intact oligodendroglial tumors are astrocytic and co-evaluation of IDH and TERTp mutation could potentially serve as an adjunct for diagnosing 1p/19q intact oligodendrogliomas.

SUBMITTER: Li YX

PROVIDER: S-EPMC5323103 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The molecular genetic alterations of oligodendroglial tumors and mixed gliomas of the central nervous system were studied in a series of 37 cases (8 oligodendrogliomas, 13 anaplastic oligodendrogliomas, 8 oligoastrocytomas, and 8 anaplastic oligoastrocytomas). A total of 180 polymorphic loci and 5 nonpolymorphic gene loci, distributed over all chromosomes, were examined by restriction fragment length polymorphism analysis. Loss of heterozygosity was most frequently observed for loci on 19q with a commonly deleted region at 19q13.2-q13.4 distal to the CYP2a gene and proximal to the D19S22 locus. The incidence of allelic loss on 19q was particularly high (81%) in oligodendroglial tumors and equal to 31% in mixed gliomas. More than 75% of the tumors with allelic deletions on 19q also showed loss of heterozygosity for loci on 1p with one tumor showing only loss of alleles distal to the NGFB gene (1p13-pter). Seven (19%) tumors had lost alleles from 17p with the deleted region including the TP53 tumor suppressor gene in all cases. Sequencing of the TP53 transcripts from exons 2 to 10, however, did not reveal mutations of the remaining allele in any of these tumors. Anaplastic oligodendrogliomas and anaplastic oligoastrocytomas demonstrated an increased incidence of additional allelic losses involving most frequently chromosomes 9p and 10. Gene amplification was detected in two anaplastic tumors, affecting the epidermal growth factor receptor gene in both cases, with additional amplification of the renin gene at 1q32 in one of these cases. In total our results indicate both differences and similarities between the molecular genetic alterations in tumors with oligodendroglial and astrocytic differentiation. The loss of genetic information from 19q and 1p as well as the rarity of TP53 mutations in oligodendroglial tumors suggests that the early events in their oncogenesis are distinct from those associated with astrocytic tumors. However, similarities are indicated by the allelic losses on 9p and 10 in the anaplastic tumors, suggesting the utilization of common pathways of progression.

Project description:BackgroundThis study aimed to assess the validity and pathophysiology of the T2/FLAIR-mismatch sign for noninvasive identification of isocitrate dehydrogenase (IDH)-mutant 1p/19q non-codeleted glioma.MethodsMagnetic resonance imaging scans from 408 consecutive patients with newly diagnosed glioma (113 lower-grade gliomas and 295 glioblastomas) were evaluated for the presence of T2/FLAIR-mismatch sign by 2 independent reviewers. Sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) were calculated to assess the performance of the T2/FLAIR-mismatch sign for identifying IDH-mutant 1p/19q non-codeleted tumors. An exploratory analysis of differences in contrast-enhancing tumor volumes, apparent diffusion coefficient (ADC) values, and relative cerebral blood volume (rCBV) values in IDH-mutant gliomas with versus without the presence of a T2/FLAIR-mismatch sign (as well as analysis of spatial differences within tumors with the presence of a T2/FLAIR-mismatch sign) was performed.ResultsThe T2/FLAIR-mismatch sign was present in 12 cases with lower-grade glioma (10.6%), all of them being IDH-mutant 1p/19q non-codeleted tumors (sensitivity = 10.9%, specificity = 100%, PPV = 100%, NPV = 3.0%, accuracy = 13.3%). There was a substantial interrater agreement to identify the T2/FLAIR-mismatch sign (Cohen's kappa = 0.75 [95% CI, 0.57-0.93]). The T2/FLAIR-mismatch sign was not identified in any other molecular subgroup, including IDH-mutant glioblastoma cases (n = 5). IDH-mutant gliomas with a T2/FLAIR-mismatch sign showed significantly higher ADC (P < .0001) and lower rCBV values (P = .0123) as compared to IDH-mutant gliomas without a T2/FLAIR-mismatch sign. Moreover, in IDH-mutant gliomas with T2/FLAIR-mismatch sign the ADC values were significantly lower in the FLAIR-hyperintense rim as compared to the FLAIR-hypointense core of the tumor (P = .0005).ConclusionsThis study confirms the high specificity of the T2/FLAIR-mismatch sign for noninvasive identification of IDH-mutant 1p/19q non-codeleted gliomas; however, sensitivity is low and applicability is limited to lower-grade gliomas. Whether the higher ADC and lower rCBV values in IDH-mutant gliomas with a T2/FLAIR-mismatch sign (as compared to those without) translate into a measurable prognostic effect requires investigation in future studies. Moreover, spatial differences in ADC values between the core and rim of tumors with a T2/FLAIR-mismatch sign potentially reflect specific distinctions in tumor cellularity and microenvironment.

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Not all 1p/19q non-codeleted oligodendroglial tumors are astrocytic.

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