Somatic POLE mutations cause an ultramutated giant cell high-grade glioma subtype with better prognosis

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dc.contributor.authorErson-Omay, E. Zeynep
dc.contributor.authorCaglayan, Ahmet Okay
dc.contributor.authorSchultz, Nikolaus
dc.contributor.authorWeinhold, Nils
dc.contributor.authorOmay, S. Bulent
dc.contributor.authorOzduman, Koray
dc.contributor.authorKoksal, Yavuz
dc.date.accessioned2020-03-26T19:07:09Z
dc.date.available2020-03-26T19:07:09Z
dc.date.issued2015
dc.departmentSelçuk Üniversitesien_US
dc.description.abstractBackground. Malignant high-grade gliomas (HGGs), including the most aggressive form, glioblastoma multiforme, show significant clinical and genomic heterogeneity. Despite recent advances, the overall survival of HGGs and their response to treatment remain poor. In order to gain further insight into disease pathophysiology by correlating genomic landscape with clinical behavior, thereby identifying distinct HGG molecular subgroups associated with improved prognosis, we performed a comprehensive genomic analysis. Methods. We analyzed and compared 720 exome-sequenced gliomas (136 from Yale, 584 from The Cancer Genome Atlas) based on their genomic, histological, and clinical features. Results. We identified a subgroup of HGGs (6 total, 4 adults and 2 children) that harbored a statistically significantly increased number of somatic mutations (mean = 9257.3 vs 76.2, P = .002). All of these "ultramutated" tumors harbored somatic mutations in the exonuclease domain of the polymerase epsilon gene (POLE), displaying a distinctive genetic profile, characterized by genomic stability and increased C-to-A transversions. Histologically, they all harbored multinucleated giant or bizarre cells, some with predominant infiltrating immune cells. One adult and both pediatric patients carried homozygous germline mutations in the mutS homolog 6 (MSH6) gene. In adults, POLE mutations were observed in patients younger than 40 years and were associated with a longer progression-free survival. Conclusions. We identified a genomically, histologically, and clinically distinct subgroup of HGGs that harbored somatic POLE mutations and carried an improved prognosis. Identification of distinctive molecular and pathological HGG phenotypes has implications not only for improved classification but also for potential targeted treatments.en_US
dc.description.sponsorshipGregory M. Kiez and Mehmet Kutman Foundationen_US
dc.description.sponsorshipThis study was supported by the Gregory M. Kiez and Mehmet Kutman Foundation.en_US
dc.identifier.doi10.1093/neuonc/nov027en_US
dc.identifier.endpage1364en_US
dc.identifier.issn1522-8517en_US
dc.identifier.issn1523-5866en_US
dc.identifier.issue10en_US
dc.identifier.pmid25740784en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage1356en_US
dc.identifier.urihttps://dx.doi.org/10.1093/neuonc/nov027
dc.identifier.urihttps://hdl.handle.net/20.500.12395/32565
dc.identifier.volume17en_US
dc.identifier.wosWOS:000364783100007en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherOXFORD UNIV PRESS INCen_US
dc.relation.ispartofNEURO-ONCOLOGYen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.selcuk20240510_oaigen_US
dc.subjectbetter prognosisen_US
dc.subjectglioblastomaen_US
dc.subjectpolymerase epsilonen_US
dc.subjectgermline MSH6 mutationen_US
dc.subjectultramutated tumoren_US
dc.titleSomatic POLE mutations cause an ultramutated giant cell high-grade glioma subtype with better prognosisen_US
dc.typeArticleen_US

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