Somatic POLE mutations cause an ultramutated giant cell high-grade glioma subtype with better prognosis
Küçük Resim Yok
Tarih
2015
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
OXFORD UNIV PRESS INC
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
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.
Açıklama
Anahtar Kelimeler
better prognosis, glioblastoma, polymerase epsilon, germline MSH6 mutation, ultramutated tumor
Kaynak
NEURO-ONCOLOGY
WoS Q Değeri
Q1
Scopus Q Değeri
Q1
Cilt
17
Sayı
10
