Deep Sequencing Identifies <i>IDH1</i> R132S Mutation in Adult Medulloblastoma

Snuderl, Matija; Triscott, Joanna; Northcott, Paul A.; Shih, Helen A.; Kong, Esther; Robinson, Hayley; Dunn, Sandra E.; Iafrate, A. John; Yip, Stephen

doi:10.1200/jco.2013.49.4864

Cited by 18 publications

(11 citation statements)

References 23 publications

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“…glioma CpG island methylator phenotype, G-CIMP) 27,28 . We identified six IDH1 R132C mutations (five SHH, one WNT), consistent with a recent case report 29 (Extended Data Fig. 6e).…”

Section: Resultssupporting

confidence: 91%

The whole-genome landscape of medulloblastoma subtypes

Northcott¹,

Buchhalter²,

Morrissy³

et al. 2017

Nature

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846

1,161

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Summary Current therapies for medulloblastoma (MB), a highly malignant childhood brain tumor, impose debilitating effects on the developing child, warranting deployment of molecularly targeted treatments with reduced toxicities. Prior studies failed to disclose the full spectrum of driver genes and molecular processes operative in MB subgroups. Herein, we detail the somatic landscape across 491 sequenced MBs and molecular heterogeneity amongst 1,256 epigenetically analyzed cases, identifying subgroup-specific driver alterations including previously unappreciated actionable targets. Driver mutations explained the majority of Group 3 and Group 4 patients, remarkably enhancing previous knowledge. Novel molecular subtypes were differentially enriched for specific driver events, including hotspot in-frame insertions targeting KBTBD4 and ‘enhancer hijacking’ driving PRDM6 activation. Thus, application of integrative genomics to an unprecedented cohort of clinical samples derived from a single childhood cancer entity disclosed a series of new cancer genes and biologically relevant subtype diversity that represent attractive therapeutic targets for treating MB patients.

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“…glioma CpG island methylator phenotype, G-CIMP) 27,28 . We identified six IDH1 R132C mutations (five SHH, one WNT), consistent with a recent case report 29 (Extended Data Fig. 6e).…”

Section: Resultssupporting

confidence: 91%

The whole-genome landscape of medulloblastoma subtypes

Northcott¹,

Buchhalter²,

Morrissy³

et al. 2017

Nature

Self Cite

846

1,161

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“…The material was then sent for DNA and RNA extraction. Aliquots of nucleic acid were used for analysis on the Ion Torrent AmpliSeq Cancer panel ( Singh et al 2013 ; Snuderl et al 2014 ) and for whole genome and transcriptome analysis on the Illumina HiSeq platform as previously described.…”

Section: Introductionmentioning

confidence: 99%

Lessons learned from the application of whole-genome analysis to the treatment of patients with advanced cancers

Laskin

Jones

Aparicio

et al. 2015

Cold Spring Harb Mol Case Stud

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122

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Given the success of targeted agents in specific populations it is expected that some degree of molecular biomarker testing will become standard of care for many, if not all, cancers. To facilitate this, cancer centers worldwide are experimenting with targeted "panel" sequencing of selected mutations. Recent advances in genomic technology enable the generation of genome-scale data sets for individual patients. Recognizing the risk, inherent in panel sequencing, of failing to detect meaningful somatic alterations, we sought to establish processes to integrate data from wholegenome analysis (WGA) into routine cancer care. Between June 2012 and August 2014, 100 adult patients with incurable cancers consented to participate in the Personalized OncoGenomics (POG) study. Fresh tumor and blood samples were obtained and used for whole-genome and RNA sequencing. Computational approaches were used to identify candidate driver mutations, genes, and pathways. Diagnostic and drug information were then sought based on these candidate "drivers." Reports were generated and discussed weekly in a multidisciplinary team setting. Other multidisciplinary working groups were assembled to establish guidelines on the interpretation, communication, and integration of individual genomic findings into patient care. Of 78 patients for whom WGA was possible, results were considered actionable in 55 cases. In 23 of these 55 cases, the patients received treatments motivated by WGA. Our experience indicates that a multidisciplinary team of clinicians and scientists can implement a paradigm in which WGA is integrated into the care of late stage cancer patients to inform systemic therapy decisions.

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“…Dysfunctional TET and/or IDH genes in uence the regulation of DNA hydroxymethylation and lead to reduction of 5hmC generation in cancers [19]. However, previous data showed that gene mutations of TET1/2/3 and IDH1/2 were extremely rare in MBs [47][48][49][50]. In this study, we found that reduced 5hmC in MBs relate to decreased expression of TET1/2 proteins, suggesting that the inactivation of TET1/2 proteins may be responsible for the altered 5hmC levels in MBs.…”

Section: Discussionmentioning

confidence: 99%

Loss of 5-Hydroxymethylcytosine as an Epigenetic Signature that Correlates with Poor Outcomes in Patients with Medulloblastoma

Zhao

Zhang

et al. 2020

Preprint

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Background: Medulloblastoma, as the most common malignant brain tumor in children, exhibits highly dysregulated DNA methylation. The novel epigenetic marker—5-hydroxymethylcytosine (5hmC) plays essential role in gene regulation during brain development and in brain tumors. However, the biological and clinical implications of 5hmC in medulloblastoma are still unclear. Methods: Here, we detected global 5hmC levels in two independent medulloblastoma patient cohorts (discovery cohort: n = 81; validation cohort: n = 171) using ultra-high performance liquid chromatography-tandem mass spectrometry analysis. Immunohistochemistry was used to identify the cell proliferation and expression of Ten-eleven translocation 1 and 2 (TET1/2). The prognostic impacts of covariates on progression-free survival (PFS) and overall survival (OS) were evaluated using multivariate Cox hazards-regression models.Results: We observed that global 5hmC levels were decreased in medulloblastomas compared to normal cerebellums (P < 0.001). Multivariate analysis showed that low 5hmC levels correlated with poor PFS and OS rates (discovery cohort: PFS: P = 0.003, OS: P = 0.002; validation cohort: PFS: P = 0.0002, OS: P = 0.001). Immunohistochemistry showed an inverse correlation between 5hmC score and Ki-67 index (r = -0.747, P < 0.0001). Moreover, 5hmC score was associated with protein expression of TET1 (r = -0.419, P = 0.003) and TET2 (r = -0.399, P = 0.005).Conclusions: Our study demonstrates that loss of 5hmC is an epigenetic biomarker in medulloblastomas. Our results indicate that 5hmC could be a candidate prognostic indicator for improving survival prediction of risk stratification in patients with medulloblastoma.

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Deep Sequencing Identifies IDH1 R132S Mutation in Adult Medulloblastoma

Cited by 18 publications

References 23 publications

The whole-genome landscape of medulloblastoma subtypes

The whole-genome landscape of medulloblastoma subtypes

Lessons learned from the application of whole-genome analysis to the treatment of patients with advanced cancers

Loss of 5-Hydroxymethylcytosine as an Epigenetic Signature that Correlates with Poor Outcomes in Patients with Medulloblastoma

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