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研究揭示协调黑色素瘤生物学和临床状态的分子集合
2020-11-25 16:28

分子集合促进协调黑色素瘤的生物学和临床状态,这一成果由美国麻省理工学院和哈佛大学广泛研究所Eliezer M. Van Allen研究小组取得。该研究成果于2020年11月23日发表在《自然-遗传学》上。

通过对1,048个黑色素瘤样品进行统一的分子和临床分析,研究人员发现了先前未知的黑色素瘤亚型(BRAF、(N)RAS、NF1三重野生型(TWT))、次生驱动基因亚型特异性偏好性和活跃突变过程中明显不同的全基因组学特性。在特定亚型中显著富集的次级驱动基因反映了其他途径的失调,例如在BRAF黑色素瘤中诱导转化生长因子-β信号转导和(N)RAS黑色素瘤中SWI / SNF复合物的失活,并且通过选择协调共突变模式对免疫检查点封锁进行选择性反应。

研究人员还确定了TWT黑色素瘤的突变情况,并揭示了该亚型中高表达DNA修复缺陷标志物,这与关键DNA修复基因的转录下调有关,并且可能对部分黑色素瘤患者重新利用之前放弃或目前尚未纳入考量的治疗方式。广泛来说,对黑色素瘤整个外显子进行统一的荟萃分析揭示了独特的分子驱动因素,这可能为黑色素瘤的生物学研究和治疗提供多重机会。

附:英文原文

Title: Integrated molecular drivers coordinate biological and clinical states in melanoma

Author: Jake R. Conway, Felix Dietlein, Amaro Taylor-Weiner, Saud AlDubayan, Natalie Vokes, Tanya Keenan, Brendan Reardon, Meng Xiao He, Claire A. Margolis, Jason L. Weirather, Rizwan Haq, Bastian Schilling, F. Stephen Hodi, Dirk Schadendorf, David Liu, Eliezer M. Van Allen

Issue&Volume: 2020-11-23

Abstract: We performed harmonized molecular and clinical analysis on 1,048 melanomas and discovered markedly different global genomic properties among subtypes (BRAF, (N)RAS, NF1, triple wild-type (TWT)), subtype-specific preferences for secondary driver genes and active mutational processes previously unreported in melanoma. Secondary driver genes significantly enriched in specific subtypes reflected preferential dysregulation of additional pathways, such as induction of transforming growth factor-β signaling in BRAF melanomas and inactivation of the SWI/SNF complex in (N)RAS melanomas, and select co-mutation patterns coordinated selective response to immune checkpoint blockade. We also defined the mutational landscape of TWT melanomas and revealed enrichment of DNA-repair-defect signatures in this subtype, which were associated with transcriptional downregulation of key DNA-repair genes, and may revive previously discarded or currently unconsidered therapeutic modalities for genomically stratified melanoma patient subsets. Broadly, harmonized meta-analysis of melanoma whole exomes revealed distinct molecular drivers that may point to multiple opportunities for biological and therapeutic investigation.

DOI: 10.1038/s41588-020-00739-1

Source: https://www.nature.com/articles/s41588-020-00739-1

Nature Genetics:《自然—遗传学》,创刊于1992年。隶属于施普林格·自然出版集团,最新IF:41.307
官方网址:https://www.nature.com/ng/
投稿链接:https://mts-ng.nature.com/cgi-bin/main.plex


本期文章:《自然—遗传学》:Online/在线发表

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