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The Misclassification of Diffuse Gliomas: Rates and Outcomes.

ABSTRACT: PURPOSE:The integrated histopathologic and molecular diagnoses of the 2016 WHO classification of central nervous system tumors have revolutionized patient care by improving diagnostic accuracy and reproducibility; however, the frequency and consequences of misclassification of histologically diagnosed diffuse gliomas are unknown. EXPERIMENTAL DESIGN:Patients with newly diagnosed ICD-O-3 (International Classification of Diseases) histologically encoded diffuse gliomas from 2010-2015 were identified from the National Cancer Database, the misclassification rates and overall survival (OS) of which were assessed by WHO grade and 1p/19q status. In addition, misclassification rates by isocitrate dehydrogenase (IDH), ATRX, and p53 statuses were examined in an analogous multi-institutional cohort of registry-encoded diffuse gliomas. RESULTS:Of 74,718 patients with diffuse glioma, only 74.4% and 78.8% of molecularly characterized WHO grade II and III oligodendrogliomas were in fact 1p/19q-codeleted. In addition, 28.9% and 36.8% of histologically encoded grade II and III "oligoastrocytomas", and 6.3% and 8.8% of grade II and III astrocytomas had 1p/19q-codeletion, thus molecularly representing oligodendrogliomas if also IDH mutant. OS significantly depended on accurate WHO grading and 1p/19q status. CONCLUSIONS:On the basis of 1p/19q, IDH, ATRX, and p53, the misclassification rates of histologically encoded oligodendrogliomas, astrocytomas, and glioblastomas are approximately 21%-35%, 6%-9%, and 9%, respectively; with significant clinical implications. Our findings suggest that when compared with historical histology-only classified data, in national registry, as well as, institutional databases, there is the potential for false-positive results in contemporary trials of molecularly classified diffuse gliomas, which could contribute to a seemingly positive phase II trial (based on historical comparison) failing at the phase III stage. Critically, findings from diffuse glioma clinical trials and historical cohorts using prior histology-only WHO schemes must be cautiously reinterpreted.

SUBMITTER: Iorgulescu JB

PROVIDER: S-EPMC6467794 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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The Misclassification of Diffuse Gliomas: Rates and Outcomes.

Iorgulescu J Bryan JB Torre Matthew M Harary Maya M Smith Timothy R TR Aizer Ayal A AA Reardon David A DA Barnholtz-Sloan Jill S JS Perry Arie A

Clinical cancer research : an official journal of the American Association for Cancer Research 20190111 8

<h4>Purpose</h4>The integrated histopathologic and molecular diagnoses of the 2016 WHO classification of central nervous system tumors have revolutionized patient care by improving diagnostic accuracy and reproducibility; however, the frequency and consequences of misclassification of histologically diagnosed diffuse gliomas are unknown.<h4>Experimental design</h4>Patients with newly diagnosed ICD-O-3 (International Classification of Diseases) histologically encoded diffuse gliomas from 2010-201 ...[more]

PMID: 30635340

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Project description:Recent studies have demonstrated that tumor-driving alterations are often different among gliomas that originated from different brain regions and have underscored the importance of analyzing molecular characteristics of gliomas stratified by brain region. Therefore, to elucidate molecular characteristics of diffuse cerebellar gliomas (DCGs), 27 adult, mostly glioblastoma cases were analyzed. Comprehensive analysis using whole-exome sequencing, RNA sequencing, and Infinium methylation array (n = 17) demonstrated their distinct molecular profile compared to gliomas in other brain regions. Frequent mutations in chromatin-modifier genes were identified including, noticeably, a truncating mutation in SETD2 (n = 4), which resulted in loss of H3K36 trimethylation and was mutually exclusive with H3F3A K27M mutation (n = 3), suggesting that epigenetic dysregulation may lead to DCG tumorigenesis. Alterations that cause loss of p53 function including TP53 mutation (n = 9), PPM1D mutation (n = 2), and a novel type of PPM1D fusion (n = 1), were also frequent. On the other hand, mutations and copy number changes commonly observed in cerebral gliomas were infrequent. DNA methylation profile analysis demonstrated that all DCGs except for those with H3F3A mutations were categorized in the "RTK I (PDGFRA)" group, and those DCGs had a gene expression signature that was highly associated with PDGFRA. Furthermore, compared with the data of 315 gliomas derived from different brain regions, promoter methylation of transcription factors genes associated with glial development showed a characteristic pattern presumably reflecting their tumor origin. Notably, SOX10, a key transcription factor associated with oligodendroglial differentiation and PDGFRA regulation, was up-regulated in both DCG and H3 K27M-mutant diffuse midline glioma, suggesting their developmental and biological commonality. In contrast, SOX10 was silenced by promoter methylation in most cerebral gliomas. These findings may suggest potential tailored targeted therapy for gliomas according to their brain region, in addition to providing molecular clues to identify the region-related cellular origin of DCGs.

Project description:BackgroundDiffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis. Mutations in IDH, TP53, and ATRX and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) have been implicated as clinically relevant markers of lower-grade gliomas.MethodsWe performed genomewide analyses of 293 lower-grade gliomas from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes.ResultsUnsupervised clustering of mutations and data from RNA, DNA-copy-number, and DNA-methylation platforms uncovered concordant classification of three robust, nonoverlapping, prognostically significant subtypes of lower-grade glioma that were captured more accurately by IDH, 1p/19q, and TP53 status than by histologic class. Patients who had lower-grade gliomas with an IDH mutation and 1p/19q codeletion had the most favorable clinical outcomes. Their gliomas harbored mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Nearly all lower-grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%). The large majority of lower-grade gliomas without an IDH mutation had genomic aberrations and clinical behavior strikingly similar to those found in primary glioblastoma.ConclusionsThe integration of genomewide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Lower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation. Most lower-grade gliomas without an IDH mutation were molecularly and clinically similar to glioblastoma. (Funded by the National Institutes of Health.).

Dataset Information

The Misclassification of Diffuse Gliomas: Rates and Outcomes.

Publications

The Misclassification of Diffuse Gliomas: Rates and Outcomes.

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