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BRAF Mutation and CDKN2A deletion define a clinically distinct subgroup of childhood secondary high-grade glioma

2015Journal article Open access
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dc.contributor.authorMistry, Matthew
dc.contributor.authorZhukova, Nataliya
dc.contributor.authorMerico, Daniele
dc.contributor.authorRakopoulos, Patricia
dc.contributor.authorKrishnatry, Rahul
dc.contributor.authorShago, Mary
dc.contributor.authorStavropoulos, James
dc.contributor.authorAlon, Noa
dc.contributor.authorPole, Jason D.
dc.contributor.authorRay, Peter N.
dc.contributor.authorNavickiene, Vilma
dc.contributor.authorMangerel, Joshua
dc.contributor.authorRemke, Marc
dc.contributor.authorBuczkowicz, Pawel
dc.contributor.authorRamaswamy, Vijay
dc.contributor.authorStucklin, Ana Guerreiro
dc.contributor.authorLi, Martin
dc.contributor.authorYoung, Edwin J.
dc.contributor.authorZhang, Cindy
dc.contributor.authorCastelo-Branco, Pedro
dc.contributor.authorBakry, Doua
dc.contributor.authorLaughlin, Suzanne
dc.contributor.authorShlien, Adam
dc.contributor.authorChan, Jennifer
dc.contributor.authorLigon, Keith L.
dc.contributor.authorRutka, James T.
dc.contributor.authorDirks, Peter B.
dc.contributor.authorTaylor, Michael D.
dc.contributor.authorGreenberg, Mark
dc.contributor.authorMalkin, David
dc.contributor.authorHuang, Annie
dc.contributor.authorBouffet, Eric
dc.contributor.authorHawkins, Cynthia E.
dc.contributor.authorTabori, Uri
dc.date.accessioned2018-12-07T14:53:30Z
dc.date.available2018-12-07T14:53:30Z
dc.date.issued2015
dc.description.abstractPurpose To uncover the genetic events leading to transformation of pediatric low-grade glioma (PLGG) to secondary high-grade glioma (sHGG). Patients and Methods We retrospectively identified patients with sHGG from a population-based cohort of 886 patients with PLGG with long clinical follow-up. Exome sequencing and array CGH were performed on available samples followed by detailed genetic analysis of the entire sHGG cohort. Clinical and outcome data of genetically distinct subgroups were obtained. Results sHGG was observed in 2.9% of PLGGs (26 of 886 patients). Patients with sHGG had a high frequency of nonsilent somatic mutations compared with patients with primary pediatric high-grade glioma (HGG; median, 25 mutations per exome; P = .0042). Alterations in chromatin-modifying genes and telomere-maintenance pathways were commonly observed, whereas no sHGG harbored the BRAF-KIAA1549 fusion. The most recurrent alterations were BRAF V600E and CDKN2A deletion in 39% and 57% of sHGGs, respectively. Importantly, all BRAF V600E and 80% of CDKN2A alterations could be traced back to their PLGG counterparts. BRAF V600E distinguished sHGG from primary HGG (P = .0023), whereas BRAF and CDKN2A alterations were less commonly observed in PLGG that did not transform (P < .001 and P < .001 respectively). PLGGs with BRAF mutations had longer latency to transformation than wild-type PLGG (median, 6.65 years [range, 3.5 to 20.3 years] v 1.59 years [range, 0.32 to 15.9 years], respectively; P = .0389). Furthermore, 5-year overall survival was 75% 15% and 29% +/- 12% for children with BRAF mutant and wild-type tumors, respectively (P = .024). Conclusion BRAF V600E mutations and CDKN2A deletions constitute a clinically distinct subtype of sHGG. The prolonged course to transformation for BRAF V600E PLGGs provides an opportunity for surgical interventions, surveillance, and targeted therapies to mitigate the outcome of sHGG. (C) 2015 by American Society of Clinical Oncology
dc.description.sponsorshipb.r.a.i.n. child Canada; JPA Foundation; Canadian Institute of Health Research Grant [MOP-123268]; Hospital for Sick Children RESTRA-COMP fund; Alex's Lemonade Stand Foundation; Society of Neuro-Oncology (International Research Development Fellowship Program); National Institutes of Health [P01CA142536]; Pediatric Low-Grade Astrocytoma Foundation
dc.description.versioninfo:eu-repo/semantics/publishedVersion
dc.identifier.doi10.1200/JCO.2014.58.3922
dc.identifier.issn0732-183X
dc.identifier.issn1527-7755
dc.identifier.urihttp://hdl.handle.net/10400.1/11546
dc.language.isoeng
dc.peerreviewedyes
dc.publisherAmerican Society of Clinical Oncology
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectIntrinsic pontine glioma
dc.subjectTert promoter mutations
dc.subjectCentral-nervous-system
dc.subjectPilocytic astrocytomas
dc.subjectGenomic landscape
dc.subjectHistone H3.3
dc.subjectFusion gene
dc.subjectTumors
dc.subjectGlioblastoma
dc.subjectDuplication
dc.titleBRAF Mutation and CDKN2A deletion define a clinically distinct subgroup of childhood secondary high-grade glioma
dc.typejournal article
dspace.entity.typePublication
oaire.citation.issue9
oaire.citation.startPage1015-+
oaire.citation.titleJournal of Clinical Oncology
oaire.citation.volume33
person.familyNameCastelo-Branco
person.givenNamePedro
person.identifier.ciencia-idE015-7F8F-5CA1
person.identifier.orcid0000-0002-3453-3978
rcaap.rightsopenAccess
rcaap.typearticle
relation.isAuthorOfPublicationbb25b5ad-1769-42be-a7d3-8fe76215aa23
relation.isAuthorOfPublication.latestForDiscoverybb25b5ad-1769-42be-a7d3-8fe76215aa23

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