Medulloblastoma genomics in the modern molecular era

Kumar, Rahul; Liu, Anthony Pak-Yin; Northcott, Paul A.

doi:10.1111/bpa.12804

Cited by 51 publications

(49 citation statements)

References 119 publications

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“…Medulloblastoma is one of the most common malignant brain tumours in children [52]. Medulloblastomas are now classified into four major molecular groups (WNTactivated, SHH-activated, Group 3, and Group 4) with distinct clinical, genetic and transcriptomic profiles [23,32,39,67]. WNT medulloblastoma patients have the best 5-year overall survival rate of over 90%, while Group 3 patients have the worst 5-year overall survival rate of merely 50% [30].…”

Section: Introductionmentioning

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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Section: Introductionmentioning

confidence: 99%

Clinical and mutational profiles of adult medulloblastoma groups

Wong

Wang

et al. 2020

acta neuropathol commun

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“…Recent advances have revealed molecular and clinical heterogeneities in MB [8,36]. Therefore, identi ng reliable biomarkers is crucial for tailoring individual treatment strategies of patients with MB.…”

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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“…Medulloblastoma (MB) is a small round blue cell tumor of the cerebellum and is one of the most common types of malignant brain tumors presented during childhood (1). MB is classified based on the histological features into three major forms of the disease: Classic, nodular/desmoplastic (ND) and large cell/anaplastic (2).…”

Section: Introductionmentioning

confidence: 99%

Production of a SCID mouse model of medulloblastoma to explore the therapeutic value of targeting tumor driver genes

2020

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Tumor driver genes are genes where structural or sequence mutations confer a selective advantage for cancer cells. The individualized targeting of tumor driver genes has become a topic of interest for tumor treatment. The prognosis for medulloblastoma (MB), a common type of malignant intracranial tumor found in children, is poor. The tumor driver genes and the corresponding targeted drugs remain to be studied. The present study analyzed tumor driver genes from tumor tissue and peripheral blood from one patient with nodular desmoplastic MB with Sonic Hedgehog activation and screened targeted drugs for the tumor driver genes. Additionally, MB tissue was successfully implanted into the SCID mouse which were then used for subsequent drug screening. The present study explored novel treatments for MB from the perspective of tumor driver genes, and may provide new ideas for choosing individualized targeted therapies for patients with MB.

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Medulloblastoma genomics in the modern molecular era

Cited by 51 publications

References 119 publications

Clinical and mutational profiles of adult medulloblastoma groups

Clinical and mutational profiles of adult medulloblastoma groups

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

Production of a SCID mouse model of medulloblastoma to explore the therapeutic value of targeting tumor driver genes

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