In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 3933-3933
Abstract:
Lower grade gliomas (LGGs, WHO grade II/III gliomas) account for approximately one third of all gliomas. Although LGGs are typically slowly progressive, their clinical course is invariably indolent and most patients ultimately succumb to death. In contrast to glioblastoma (GBM), our knowledge about the genetic lesions and clonal evolution in LGG is still incomplete. So, to obtain a complete registry of gene mutations involved in LGG pathogenesis and their role in clonal evolution, we performed whole exome sequencing (WES) and/or targeted sequencing of 335 LGG cases. Clonal evolution in LGG was investigated using paired primary/relapsed tumor specimens from 10 cases as well as multiple tumor specimens (median 5) from 4 cases. Massive parallel sequencing revealed LGGs were clearly grouped into three subgroups with or without IDH1/2 mutation and 1p19q loss of heterozygous (LOH). Type I tumor with IDH1/2 mutation and 1p19q LOH had a most favorable survival and harbored mutations in TERT promoter, CIC, FUBP1 and NOTCH1. Type II tumor with IDH1/2 mutant/1p19q intact subtype represented TP53 bialleleic inactivation and/or ATRX mutations. Type III tumor with IDH1/2 intact showed GBM like mutation profile and poor prognosis. Large scale samples allowed to obviously detect strong positive/negative correlations with each other driver genes. Extensive analysis of variant allele frequencies among co-existing mutations revealed temporal orders of gene mutations in each subtypes. Multi regional/time-points sampling analysis suppoted mutational order and revealed regional and special heterogeneity with tumor evolution in LGGs. LGG contiguously developed and generated heterogeneity through acquiring new mutations in a complex but ordered fashion. In conclusion, our findings delineated the landscape of gene mutations in LGG. LGG had mutually exclusive mutational patterns with hierarchical order in discrete subtypes. IDH1/2 and TERT promoter mutations and 1p19q LOH were thought to exist in the major clone and important role in tumor initiation. In contrast, common occurrence of parallel mutations found in TP53, ATRX, CIC, FUBP1 and NOTCH1 genes indicated central roles of these mutations in LGG development. Citation Format: Hiromichi Suzuki, Kosuke Aoki, Kenichi Chiba, Yusuke Sato, Yusuke Shiozawa, Yuichi Shiraishi, Atsushi Niida, Teppei Shimamura, Masashi Sanada, Satoru Miyano, Toshihiko Wakabayashi, Atsushi Natsume, Seishi Ogawa. The landscape and clonal architecture in lower grade glioma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3933. doi:10.1158/1538-7445.AM2015-3933
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2015-3933
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2015
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
