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

E. Zeynep Erson-Omay, Ahmet Okay Cąʇlayan, Nikolaus Schultz, Nils Weinhold, S. Bülent Omay, Koray Özduman, Yavuz Köksal, Jie Li, Akdes Serin Harmancl, Victoria Clark, Geneive Carrión-Grant, Jacob Baranoski, Caner Cąʇlar, Tanyeri Barak, Süleyman Coşkun, Burçin Baran, Doʇan Köse, Jia Sun, Mehmet Baklrcloʇlu, Jennifer Moliterno Günel & 8 others M. Necmettin Pamir, Ketu Mishra-Gorur, Kaya Bilguvar, Katsuhito Yasuno, Alexander Vortmeyer, Anita J. Huttner, Chris Sander, Murat Günel

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

Background 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.

Original languageEnglish (US)
Pages (from-to)1356-1364
Number of pages9
JournalNeuro-Oncology
Volume17
Issue number10
DOIs
StatePublished - Oct 1 2015
Externally publishedYes

Fingerprint

Giant Cells
Glioma
Mutation
Genes
Exome
Exonucleases
Germ-Line Mutation
Atlases
Genomic Instability
Glioblastoma
Disease-Free Survival
Neoplasms
Genome
Pediatrics
Phenotype
Survival
Therapeutics

Keywords

  • ultramutated tumor

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

Cite this

Erson-Omay, E. Z., Cąʇlayan, A. O., Schultz, N., Weinhold, N., Omay, S. B., Özduman, K., ... Günel, M. (2015). Somatic POLE mutations cause an ultramutated giant cell high-grade glioma subtype with better prognosis. Neuro-Oncology, 17(10), 1356-1364. https://doi.org/10.1093/neuonc/nov027

Somatic POLE mutations cause an ultramutated giant cell high-grade glioma subtype with better prognosis. / Erson-Omay, E. Zeynep; Cąʇlayan, Ahmet Okay; Schultz, Nikolaus; Weinhold, Nils; Omay, S. Bülent; Özduman, Koray; Köksal, Yavuz; Li, Jie; Serin Harmancl, Akdes; Clark, Victoria; Carrión-Grant, Geneive; Baranoski, Jacob; Cąʇlar, Caner; Barak, Tanyeri; Coşkun, Süleyman; Baran, Burçin; Köse, Doʇan; Sun, Jia; Baklrcloʇlu, Mehmet; Moliterno Günel, Jennifer; Pamir, M. Necmettin; Mishra-Gorur, Ketu; Bilguvar, Kaya; Yasuno, Katsuhito; Vortmeyer, Alexander; Huttner, Anita J.; Sander, Chris; Günel, Murat.

In: Neuro-Oncology, Vol. 17, No. 10, 01.10.2015, p. 1356-1364.

Research output: Contribution to journalArticle

Erson-Omay, EZ, Cąʇlayan, AO, Schultz, N, Weinhold, N, Omay, SB, Özduman, K, Köksal, Y, Li, J, Serin Harmancl, A, Clark, V, Carrión-Grant, G, Baranoski, J, Cąʇlar, C, Barak, T, Coşkun, S, Baran, B, Köse, D, Sun, J, Baklrcloʇlu, M, Moliterno Günel, J, Pamir, MN, Mishra-Gorur, K, Bilguvar, K, Yasuno, K, Vortmeyer, A, Huttner, AJ, Sander, C & Günel, M 2015, 'Somatic POLE mutations cause an ultramutated giant cell high-grade glioma subtype with better prognosis', Neuro-Oncology, vol. 17, no. 10, pp. 1356-1364. https://doi.org/10.1093/neuonc/nov027
Erson-Omay EZ, Cąʇlayan AO, Schultz N, Weinhold N, Omay SB, Özduman K et al. Somatic POLE mutations cause an ultramutated giant cell high-grade glioma subtype with better prognosis. Neuro-Oncology. 2015 Oct 1;17(10):1356-1364. https://doi.org/10.1093/neuonc/nov027
Erson-Omay, E. Zeynep ; Cąʇlayan, Ahmet Okay ; Schultz, Nikolaus ; Weinhold, Nils ; Omay, S. Bülent ; Özduman, Koray ; Köksal, Yavuz ; Li, Jie ; Serin Harmancl, Akdes ; Clark, Victoria ; Carrión-Grant, Geneive ; Baranoski, Jacob ; Cąʇlar, Caner ; Barak, Tanyeri ; Coşkun, Süleyman ; Baran, Burçin ; Köse, Doʇan ; Sun, Jia ; Baklrcloʇlu, Mehmet ; Moliterno Günel, Jennifer ; Pamir, M. Necmettin ; Mishra-Gorur, Ketu ; Bilguvar, Kaya ; Yasuno, Katsuhito ; Vortmeyer, Alexander ; Huttner, Anita J. ; Sander, Chris ; Günel, Murat. / Somatic POLE mutations cause an ultramutated giant cell high-grade glioma subtype with better prognosis. In: Neuro-Oncology. 2015 ; Vol. 17, No. 10. pp. 1356-1364.
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TY - JOUR

T1 - Somatic POLE mutations cause an ultramutated giant cell high-grade glioma subtype with better prognosis

AU - Erson-Omay, E. Zeynep

AU - Cąʇlayan, Ahmet Okay

AU - Schultz, Nikolaus

AU - Weinhold, Nils

AU - Omay, S. Bülent

AU - Özduman, Koray

AU - Köksal, Yavuz

AU - Li, Jie

AU - Serin Harmancl, Akdes

AU - Clark, Victoria

AU - Carrión-Grant, Geneive

AU - Baranoski, Jacob

AU - Cąʇlar, Caner

AU - Barak, Tanyeri

AU - Coşkun, Süleyman

AU - Baran, Burçin

AU - Köse, Doʇan

AU - Sun, Jia

AU - Baklrcloʇlu, Mehmet

AU - Moliterno Günel, Jennifer

AU - Pamir, M. Necmettin

AU - Mishra-Gorur, Ketu

AU - Bilguvar, Kaya

AU - Yasuno, Katsuhito

AU - Vortmeyer, Alexander

AU - Huttner, Anita J.

AU - Sander, Chris

AU - Günel, Murat

PY - 2015/10/1

Y1 - 2015/10/1

N2 - Background 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.

AB - Background 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.

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DO - 10.1093/neuonc/nov027

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