Prognostic relevance of genetic alterations in diffuse lower-grade gliomas

• Published in: Neuro-oncology (Charlottesville, Va.) Vol. 20; no. 1; pp. 66 - 77
• Main Authors: Aoki, Kosuke, Nakamura, Hideo, Suzuki, Hiromichi, Matsuo, Keitaro, Kataoka, Keisuke, Shimamura, Teppei, Motomura, Kazuya, Ohka, Fumiharu, Shiina, Satoshi, Yamamoto, Takashi, Nagata, Yasunobu, Yoshizato, Tetsuichi, Mizoguchi, Masahiro, Abe, Tatsuya, Momii, Yasutomo, Muragaki, Yoshihiro, Watanabe, Reiko, Ito, Ichiro, Sanada, Masashi, Yajima, Hironori, Morita, Naoya, Takeuchi, Ichiro, Miyano, Satoru, Wakabayashi, Toshihiko, Ogawa, Seishi, Natsume, Atsushi
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 10.01.2018
• Subjects: Basic and Translational Investigations; prognostic factor; diffuse lower-grade glioma; genetic alteration
• DOI: 10.1093/neuonc/nox132
• ISSN: 1522-8517; 1523-5866

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.