期刊
NEURO-ONCOLOGY
卷 20, 期 1, 页码 66-77出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/neuonc/nox132
关键词
diffuse lower-grade glioma; genetic alteration; prognostic factor
资金
- Japan Brain Foundation
- Funding Program for World-Leading Innovative Research and Development on Science and Technology
- Project for Development of Innovative Research on Cancer Therapeutics from the Japan Agency for Medical Research and Development, AMED [15cm0106056h0005, 16cm0106501h0001]
- High Performance Computing Infrastructure System Research Project [hp150232]
- [22134006]
- [15H05909]
- [23107010]
- [15H06339]
- Grants-in-Aid for Scientific Research [16K10761, 15K10337, 17K16643] Funding Source: KAKEN
Diffuse lower-grade gliomas (LGGs) are genetically classified into 3 distinct subtypes based on isocitrate dehydrogenase (IDH) mutation status and codeletion of chromosome 1p and 19q (1p/19q). However, the subtype-specific effects of additional genetic lesions on survival are largely unknown. Using Cox proportional hazards regression modeling, we investigated the subtype-specific effects of genetic alterations and clinicopathological factors on survival in each LGG subtype, in a Japanese cohort of LGG cases fully genotyped for driver mutations and copy number variations associated with LGGs (n = 308). The results were validated using a dataset from 414 LGG cases available from The Cancer Genome Atlas (TCGA). In Oligodendroglioma, IDH-mutant and 1p/19q codeleted, NOTCH1 mutations (P = 0.0041) and incomplete resection (P = 0.0019) were significantly associated with shorter survival. In Astrocytoma, IDH-mutant, PIK3R1 mutations (P = 0.0014) and altered retinoblastoma pathway genes (RB1, CDKN2A, and CDK4) (P = 0.013) were independent predictors of poor survival. In IDH-wildtype LGGs, co-occurrence of 7p gain, 10q loss, mutation in the TERT promoter (P = 0.024), and grade III histology (P < 0.0001) independently predicted poor survival. IDH-wildtype LGGs without any of these factors were diagnosed at a younger age (P = 0.042), and were less likely to have genetic lesions characteristic of glioblastoma, in comparison with other IDH-wildtype LGGs, suggesting that they likely represented biologically different subtypes. These results were largely confirmed in the cohort of TCGA. Subtype-specific genetic lesions can be used to stratify patients within each LGG subtype. enabling better prognostication and management.
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