Whole‐exome sequencing revealed mutational profiles of giant cell glioblastomas

Shi, Zhifeng; Li, Kay Ka‐Wai; Kwan, Johnny S. H.; Yang, Rui; Aibaidula, Abudumijiti; Tang, Qisheng; Bao, Yifeng; Mao, Ying; Chen, Hong; Ng, Ho‐Keung

doi:10.1111/bpa.12720

Cited by 16 publications

(13 citation statements)

References 56 publications

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“…Therefore, this study suggests that ultra-mutated GBMs might represent a subgroup of giant cell GBMs, which is not only characterized by POLE mutations. However, giant cell enrichment is not a unique feature of ultra-mutated GBMs and no ultra-mutated cases were found in a cohort of giant cell GBMs in a recent study [32].…”

Section: Discussionmentioning

confidence: 99%

Ultra-Mutation in IDH Wild-Type Glioblastomas of Patients Younger than 55 Years is Associated with Defective Mismatch Repair, Microsatellite Instability, and Giant Cell Enrichment

Barresi

Simbolo

Mafficini

et al. 2019

Cancers

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Background: Glioblastomas (GBMs) are classified into isocitrate dehydrogenase (IDH) mutants and IDH wild-types (IDH-wt). This study aimed at identifying the mutational assets of IDH-wt GBMs in patients aged 18–54 years for which limited data are available. Methods: Sixteen IDH-wt GBMs from adults < 55 years old were explored for mutations, copy number variations, tumour mutational load (TML), and mutational spectrum by a 409 genes TML panel. Results: Eight (50%) IDH-wt GBMs were hypermutated (TML > 9 mutations/Mb) and two (12.5%) were ultra-mutated (TML > 100 mutations/Mb). One ultra-mutated GBM had microsatellite instability (MSI), a somatic MSH6 mutation, and a germline POLE mutation. The other ultra-mutated GBMs had MSI and two somatic mutations in MSH2. Both ultra-mutated GBMs featured at least 25% giant cells. The overall survival of eight patients with hypermutated GBMs was significantly longer than that of patients with non-hypermutated GBMs (p = 0.04). Conclusions: We identified a hyper-mutated subgroup among IDH-wt GBMs in adults < 55 years that had improved prognosis. Two cases were ultra-mutated and characterized by the presence of at least 25% giant cells, MMR mutations, and MSI. Since high TML has been associated with response to immune checkpoint inhibition in paediatric gliomas, the identification of a subtype of ultra-mutated IDH-wt GBM may have implications for immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Ultra-Mutation in IDH Wild-Type Glioblastomas of Patients Younger than 55 Years is Associated with Defective Mismatch Repair, Microsatellite Instability, and Giant Cell Enrichment

Barresi

Simbolo

Mafficini

et al. 2019

Cancers

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“…No information is available regarding the specific molecular or phenotypic characteristics of LS-(or CMMRD)-related brain tumors. The histological variant of glioblastoma with multinucleated giant cells is also not specific [106,108,109], but given its rarity (approximately 1% of all glioblastomas), there may be a particular interest in proposing a constitutional MMR gene (and POLE) analysis in patients with a giant cell glioblastoma.…”

Section: Brain Tumorsmentioning

confidence: 99%

Diagnosis of Lynch Syndrome and Strategies to Distinguish Lynch-Related Tumors from Sporadic MSI/dMMR Tumors

Leclerc

Vermaut²,

Buisine

2021

Cancers

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Microsatellite instability (MSI) is a hallmark of Lynch syndrome (LS)-related tumors but is not specific to it, as approximately 80% of MSI/mismatch repair-deficient (dMMR) tumors are sporadic. Methods leading to the diagnosis of LS have considerably evolved in recent years and so have tumoral tests for LS screening and for the discrimination of LS-related to MSI-sporadic tumors. In this review, we address the hallmarks of LS, including the clinical, histopathological, and molecular features. We present recent advances in diagnostic and screening strategies to identify LS patients. We also discuss the pitfalls associated with the current strategies, which should be taken into account to improve the diagnosis of LS and avoid inappropriate clinical management.

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“…A previous whole genome sequencing study identified the TERT promoter as the only non-coding region that is recurrently mutated in medulloblastoma [45]. Accordingly, we performed Sanger sequencing to evaluate the mutational hotspots of TERT promoter, C228T and C250T (124 and 146 bp upstream of the ATG start site respectively), as previously described [1,8,9,37,64,71,72].…”

Section: Sanger Sequencing For Tert Promoter Hotspot Mutationsmentioning

confidence: 99%

Clinical and mutational profiles of adult medulloblastoma groups

Wong

Wang

et al. 2020

acta neuropathol commun

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Adult medulloblastomas are clinically and molecularly understudied due to their rarity. We performed molecular grouping, targeted sequencing, and TERT promoter Sanger sequencing on a cohort of 99 adult medulloblastomas. SHH made up 50% of the cohort, whereas Group 3 (13%) was present in comparable proportion to WNT (19%) and Group 4 (18%). In contrast to paediatric medulloblastomas, molecular groups had no prognostic impact in our adult cohort (p = 0.877). Most frequently mutated genes were TERT (including promoter mutations, mutated in 36% cases), chromatin modifiers KMT2D (31%) and KMT2C (30%), TCF4 (31%), PTCH1 (27%) and DDX3X (24%). Adult WNT patients showed enrichment of TP53 mutations (6/15 WNT cases), and 3/6 TP53-mutant WNT tumours were of large cell/anaplastic histology. Adult SHH medulloblastomas had frequent upstream pathway alterations (PTCH1 and SMO mutations) and few downstream alterations (SUFU mutations, MYCN amplifications). TERT promoter mutations were found in 72% of adult SHH patients, and were restricted to this group. Adult Group 3 tumours lacked hallmark MYC amplifications, but had recurrent mutations in KBTBD4 and NOTCH1. Adult Group 4 tumours harboured recurrent mutations in TCF4 and chromatin modifier genes. Overall, amplifications of MYC and MYCN were rare (3%). Since molecular groups were not prognostic, alternative prognostic markers are needed for adult medulloblastoma. KMT2C mutations were frequently found across molecular groups and were associated with poor survival (p = 0.002). Multivariate analysis identified histological type (p = 0.026), metastasis (p = 0.031) and KMT2C mutational status (p = 0.046) as independent prognosticators in our cohort. In summary, we identified distinct clinical and mutational characteristics of adult medulloblastomas that will inform their risk stratification and treatment.

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Whole‐exome sequencing revealed mutational profiles of giant cell glioblastomas

Cited by 16 publications

References 56 publications

Ultra-Mutation in IDH Wild-Type Glioblastomas of Patients Younger than 55 Years is Associated with Defective Mismatch Repair, Microsatellite Instability, and Giant Cell Enrichment

Ultra-Mutation in IDH Wild-Type Glioblastomas of Patients Younger than 55 Years is Associated with Defective Mismatch Repair, Microsatellite Instability, and Giant Cell Enrichment

Diagnosis of Lynch Syndrome and Strategies to Distinguish Lynch-Related Tumors from Sporadic MSI/dMMR Tumors

Clinical and mutational profiles of adult medulloblastoma groups

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