Molecular Correlates of Long Survival in IDH-Wildtype Glioblastoma Cohorts

Galbraith, Kristyn; Kumar, Ashwani; Abdullah, Kalil G.; Walker, Jamie M.; Adams, Steven H; Prior, Timothy; Dimentberg, Ryan; Henderson, Fraser; Mirchia, Kanish; Sathe, Adwait Amod; Viapiano, Mariano S.; Chin, Lawrence S.; Corona, Robert John; Hatanpaa, Kimmo J.; Snuderl, Matija; Xing, Chao; Brem, Steven; Richardson, Timothy E.

doi:10.1093/jnen/nlaa059

Cited by 37 publications

(32 citation statements)

References 65 publications

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“…Similar to previous studies [137,140], our results indicate that these long-surviving GBM patients are significantly younger and have lower overall somatic mutation burden. Additionally, 19+/20+ only conferred a prognostic benefit in the IDH-wildtype GBMs with at least one of the cIMPACT-NOW 3 factors [129] .…”

Section: Idh-wildtype Glioblastomamentioning

confidence: 96%

“…Elevated CNV correlates with worse clinical outcome than IDH-mutant lowergrade gliomas, however, no in-group effects [52,129] CDK4/MDM2 Co-amplification is correlated with worse clinical outcome [120,121,139] EGFR/PTEN/CDKN2A Co-alterations of these three genes is correlated with worse clinical outcome [141] PIK3CA…”

Section: Idh-wildtype Glioblastomamentioning

confidence: 99%

“…However, caution should be exercised in assigning grade IV based solely on the presence of an H3 K27M mutation since studies have shown its presence in lower grade tumors such as pilocytic astrocytoma and glioneuronal tumors or tumors in non-midline locations that do not necessarily have poor clinical outcomes [178][179][180][181]. BRAF (V600E) Mutation is correlated with better outcome [152,153] EGFR amplification, 7+/10−, TERTp mutation Alteration of any of these factors correlates with worse clinical outcome; GBM-C0 status correlates with better clinical outcome [129] Total copy number variation (CNV)…”

Section: Idh-wildtype Glioblastomamentioning

confidence: 99%

“…Randomly selected IDH-wildtype grade II-III astrocytoma have statistically identical prognoses compared to IDH-wildtype glioblastoma [ 36 , 43 , 52 ], and many tumors originally diagnosed as IDH-wildtype lower-grade astrocytomas can now be separated into other diagnostic categories [ 124 , 125 ]. These lower-grade IDH-wildtype astrocytomas frequently have specific molecular alterations characteristic of IDH-wildtype glioblastoma, including high frequency of EGFR amplification, combined gain of chromosome 7 with loss of chromosome 10 (7+/10−), TERT p mutation, and tumors with these three factors have similar outcomes to IDH-wildtype glioblastoma, while lower-grade tumors without these characteristic alterations have significantly better clinical outcomes [ 36 , 43 , 88 , 126 , 127 , 128 , 129 ]. New cIMPACT-NOW update 3 clinical guidelines now recommend the diagnosis of “ diffuse astrocytic glioma, IDH-wildtype with molecular features of glioblastoma “, for IDH wildtype astrocytomas lacking the histologic features of glioblastoma but having one or more of these “molecular grade IV” features [ 130 ], and this has been confirmed in subsequent validation studies [ 131 ].…”

Section: Idh-wildtype Lower-grade Astrocytomamentioning

confidence: 99%

“…Recently, we have shown that alterations in EGFR , 7+/10−, and TERT p mutations may have similar prognostic significance in IDH-wildtype GBM as in IDH-wildtype lower-grade tumors in both univariate and multivariate analysis [ 129 ] . There is significantly longer overall survival in tumors without any of these cIMPACT-NOW update 3 factors (GBM-C0) compared to tumors with at least one factor (GBM-C1-3).…”

Section: Idh-wildtype Glioblastomamentioning

confidence: 99%

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Beyond IDH-Mutation: Emerging Molecular Diagnostic and Prognostic Features in Adult Diffuse Gliomas

Mirchia

Richardson

2020

Cancers

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Diffuse gliomas are among the most common adult central nervous system tumors with an annual incidence of more than 16,000 cases in the United States. Until very recently, the diagnosis of these tumors was based solely on morphologic features, however, with the publication of the WHO Classification of Tumours of the Central Nervous System, revised 4th edition in 2016, certain molecular features are now included in the official diagnostic and grading system. One of the most significant of these changes has been the division of adult astrocytomas into IDH-wildtype and IDH-mutant categories in addition to histologic grade as part of the main-line diagnosis, although a great deal of heterogeneity in the clinical outcome still remains to be explained within these categories. Since then, numerous groups have been working to identify additional biomarkers and prognostic factors in diffuse gliomas to help further stratify these tumors in hopes of producing a more complete grading system, as well as understanding the underlying biology that results in differing outcomes. The field of neuro-oncology is currently in the midst of a “molecular revolution” in which increasing emphasis is being placed on genetic and epigenetic features driving current diagnostic, prognostic, and predictive considerations. In this review, we focus on recent advances in adult diffuse glioma biomarkers and prognostic factors and summarize the state of the field.

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Section: Idh-wildtype Glioblastomamentioning

confidence: 96%

Section: Idh-wildtype Glioblastomamentioning

confidence: 99%

Section: Idh-wildtype Glioblastomamentioning

confidence: 99%

Section: Idh-wildtype Lower-grade Astrocytomamentioning

confidence: 99%

Section: Idh-wildtype Glioblastomamentioning

confidence: 99%

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Beyond IDH-Mutation: Emerging Molecular Diagnostic and Prognostic Features in Adult Diffuse Gliomas

Mirchia

Richardson

2020

Cancers

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Genetic and epigenetic instability as an underlying driver of progression and aggressive behavior in IDH-mutant astrocytoma

Richardson,

Walker,

Hambardzumyan

et al. 2024

Acta Neuropathol

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In recent years, the classification of adult-type diffuse gliomas has undergone a revolution, wherein specific molecular features now represent defining diagnostic criteria of IDH-wild-type glioblastomas, IDH-mutant astrocytomas, and IDH-mutant 1p/19q-codeleted oligodendrogliomas. With the introduction of the 2021 WHO CNS classification, additional molecular alterations are now integrated into the grading of these tumors, given equal weight to traditional histologic features. However, there remains a great deal of heterogeneity in patient outcome even within these established tumor subclassifications that is unexplained by currently codified molecular alterations, particularly in the IDH-mutant astrocytoma category. There is also significant intercellular genetic and epigenetic heterogeneity and plasticity with resulting phenotypic heterogeneity, making these tumors remarkably adaptable and robust, and presenting a significant barrier to the design of effective therapeutics. Herein, we review the mechanisms and consequences of genetic and epigenetic instability, including chromosomal instability (CIN), microsatellite instability (MSI)/mismatch repair (MMR) deficits, and epigenetic instability, in the underlying biology, tumorigenesis, and progression of IDH-mutant astrocytomas. We also discuss the contribution of recent high-resolution transcriptomics studies toward defining tumor heterogeneity with single-cell resolution. While intratumoral heterogeneity is a well-known feature of diffuse gliomas, the contribution of these various processes has only recently been considered as a potential driver of tumor aggressiveness. CIN has an independent, adverse effect on patient survival, similar to the effect of histologic grade and homozygous CDKN2A deletion, while MMR mutation is only associated with poor overall survival in univariate analysis but is highly correlated with higher histologic/molecular grade and other aggressive features. These forms of genomic instability, which may significantly affect the natural progression of these tumors, response to therapy, and ultimately clinical outcome for patients, are potentially measurable features which could aid in diagnosis, grading, prognosis, and development of personalized therapeutics.

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