Abstract 4751: Genetic subtype-specific prognostic significance of genetic alterations in lower-grade gliomas
Authors: Aoki Kosuke , Suzuki Hiromichi , Nakamura Hideo , Matsuo Keitaro , Motomura Kazuya , Ohka Fumiharu , Mizoguchi Masahiro , Momii Yasutomo , Muragaki Yasuhiro , Miyano Satoru , Wakabayashi Toshihiko , Natsume Atsushi , Ogawa Seishi 
Published: July 2016

Abstract
BACKGROUND:
Lower-grade gliomas (WHO grade II and III gliomas) are usually slowly progressive but rarely curable brain caners, for which optimal therapy is still controversial. Recently, we have delineated a comprehensive picture of genetic alterations in lower-grade gliomas and revealed that they could be clearly classified into three genetic subtypes characterized by distinct genetic and clinical features: IDH1/2 mutated tumors with 1p/19q co-deletion (Type−I), IDH1/2 mutated tumors without 1p/19q co-deletion (Type−II) and IDH1/2 wild-type tumors (Type−III). Median survival of each genetic subtype is 16.4, 7.77, and 2.12 years in Type−I, −II, and −III tumors, respectively. Given a higher layer of inter-tumor heterogeneity inferred from the presence of additional genetic lesions on each subtype, there still remains a possibility that within each subtype, we could find one or more subgroups showing distinct biological behaviors and clinical outcomes. In the current study, we analyzed a large data set of patients with lower-grade gliomas fully genotyped for major genetic lesions to determine the prognostic significance of additional genetic alterations..
METHODS:
We analyzed genetic alterations detected by exome and/or targeted sequencing as well as SNP-array karyotyping obtained from clinically well-annotated 724 patients aged ≥18 years with supratentorial lower-grade gliomas from the Japan and The Cancer Genome Atlas (TCGA) cohorts. We performed univariate and multivariate Cox hazard proportional analyses for overall survival; multivariate models incorporated age at the time of surgery (≥60 vs. &lt;60 years old), WHO grade (grade II vs. III), and extent of resection (gross total resection vs. partial resection or biopsy) with stratification of cohorts (Japan or TCGA) and were performed with stepwise selection of variables based on the Akaike information criterion.
RESULTS:
In the multivariate Cox proportional-hazards regression analysis, we revealed that several genetic alterations have subtype-specific prognostic significance: NOTCH1 mutation in Type-I [hazard ratio (HR) = 2.57, 95% confidence interval (CI) = 1.40-4.70], high-level focal amplification of CDK4 [HR = 9.40, 95% CI = 3.08-28.7], PIK3R1 mutation [HR = 8.13, 95% CI = 2.70-24.52], and loss of chromosome 9p [HR = 1.98, 95% CI = 1.16-3.38] in Type-II, and loss of chromosome 10 [HR = 2.26, 95% CI = 1.28-3.97] in Type-III tumors. In Type-III tumors, WHO grade [HR = 5.79, 95% CI = 2.79-12.0] showed a much higher prognostic value than other prognostic factors. Most of these genetic alterations are components of three major signaling pathways or copy number variations frequently affected in glioblastomas, suggesting a close link of disease progression to glioblastoma pathophysiology.
CONCLUSIONS:
Subtype-specific genetic lesions can be used to further stratify patients in each genetic subtype for overall survival to improve management of lower-grade gliomas.
Citation Format: Kosuke Aoki, Hiromichi Suzuki, Hideo Nakamura, Keitaro Matsuo, Kazuya Motomura, Fumiharu Ohka, Masahiro Mizoguchi, Yasutomo Momii, Yasuhiro Muragaki, Satoru Miyano, Toshihiko Wakabayashi, Atsushi Natsume, Seishi Ogawa. Genetic subtype-specific prognostic significance of genetic alterations in lower-grade gliomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4751.