Mechanisms and therapeutic implications of hypermutation in gliomas

doi:10.1038/s41586-020-2209-9

GSTDTAP > 地球科学

DOI	10.1038/s41586-020-2209-9
	Mechanisms and therapeutic implications of hypermutation in gliomas
	Feng, Kaibo 1; Quevedo, Raundi E.1; Kohrt, Jeffrey T.2; Oderinde, Martins S.3; Reilly, Usa 2; White, M. Christina 1
	2020-03-16
发表期刊	NATURE
ISSN	0028-0836
EISSN	1476-4687
出版年	2020
卷号	580 期号:7804 页码:517-+
文章类型	Article
语种	英语
国家	USA; France; England
英文关键词	A high tumour mutational burden (hypermutation) is observed in some gliomas(1-5) however, the mechanisms by which hypermutation develops and whether it predicts the response to immunotherapy are poorly understood. Here we comprehensively analyse the molecular determinants of mutational burden and signatures in 10,294 gliomas. We delineate two main pathways to hypermutation: a de novo pathway associated with constitutional defects in DNA polymerase and mismatch repair (MMR) genes, and a more common post-treatment pathway, associated with acquired resistance driven by MMR defects in chemotherapy-sensitive gliomas that recur after treatment with the chemotherapy drug temozolomide. Experimentally, the mutational signature of post-treatment hypermutated gliomas was recapitulated by temozolomide-induced damage in cells with MMR deficiency. MMR-deficient gliomas were characterized by a lack of prominent T cell infiltrates, extensive intratumoral heterogeneity, poor patient survival and a low rate of response to PD-1 blockade. Moreover, although bulk analyses did not detect microsatellite instability in MMR-deficient gliomas, single-cell whole-genome sequencing analysis of post-treatment hypermutated glioma cells identified microsatellite mutations. These results show that chemotherapy can drive the acquisition of hypermutated populations without promoting a response to PD-1 blockade and supports the diagnostic use of mutational burden and signatures in cancer. Temozolomide therapy seems to lead to mismatch repair deficiency and hypermutation in gliomas, but not to an increase in response to immunotherapy.
领域	地球科学 ; 气候变化 ; 资源环境
收录类别	SCI-E
WOS记录号	WOS:000528065800026
WOS关键词	MUTATIONAL LANDSCAPE ; PD-1 BLOCKADE ; DNA-REPAIR ; GLIOBLASTOMA ; TEMOZOLOMIDE ; GENERATION ; MSH6 ; EVOLUTION ; PROGRESSION ; SENSITIVITY
WOS类目	Multidisciplinary Sciences
WOS研究方向	Science & Technology - Other Topics
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/281386
专题	地球科学资源环境科学气候变化
作者单位	1.Univ Illinois, Dept Chem, Roger Adams Lab, Urbana, IL 61801 USA; 2.Pfizer Worldwide Res & Dev, Groton Labs, Groton, CT USA; 3.Bristol Myers Squibb Co, Res & Dev, Lawrenceville, NJ USA
推荐引用方式 GB/T 7714	Feng, Kaibo,Quevedo, Raundi E.,Kohrt, Jeffrey T.,et al. Mechanisms and therapeutic implications of hypermutation in gliomas[J]. NATURE,2020,580(7804):517-+.
APA	Feng, Kaibo,Quevedo, Raundi E.,Kohrt, Jeffrey T.,Oderinde, Martins S.,Reilly, Usa,&White, M. Christina.(2020).Mechanisms and therapeutic implications of hypermutation in gliomas.NATURE,580(7804),517-+.
MLA	Feng, Kaibo,et al."Mechanisms and therapeutic implications of hypermutation in gliomas".NATURE 580.7804(2020):517-+.