Somatic POLE mutations cause an ultramutated giant cell high-grade glioma subtype with better prognosis Journal Article
| Authors: | Erson-Omay, E. Z.; Cąʇlayan, A. O.; Schultz, N.; Weinhold, N.; Omay, S. B.; 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, M. N.; Mishra-Gorur, K.; Bilgüvar, K.; Yasuno, K.; Vortmeyer, A.; Huttner, A. J.; Sander, C.; Günel, M. |
| Article Title: | Somatic POLE mutations cause an ultramutated giant cell high-grade glioma subtype with better prognosis |
| 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. © 2015 The Author(s). |
| Keywords: | adult; child; clinical article; somatic mutation; clinical feature; glioma; genetic analysis; phenotype; progression free survival; histology; homozygosity; clonal variation; genomic instability; glioblastoma; exonuclease; tumor gene; giant cell; immunocompetent cell; copy number variation; exome; msh6 gene; prognosis; human; article; ultramutated tumor; pole gene; ultramutated giant cell high grade glioma |
| Journal Title: | Neuro-Oncology |
| Volume: | 17 |
| Issue: | 10 |
| ISSN: | 1522-8517 |
| Publisher: | Oxford University Press |
| Date Published: | 2015-10-01 |
| Start Page: | 1356 |
| End Page: | 1364 |
| Language: | English |
| DOI: | 10.1093/neuonc/nov027 |
| PROVIDER: | scopus |
| PMCID: | PMC4578578 |
| PUBMED: | 25740784 |
| DOI/URL: | |
| Notes: | Export Date: 2 November 2015 -- Source: Scopus |
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