Integrated molecular drivers coordinate biological and clinical states in melanoma.
Integrated molecular drivers coordinate biological and clinical states in melanoma.
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DOI：
10.1038/s41588-020-00739-1
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发表时间：
2020-12
期刊：
影响因子：
30.8
通讯作者：
Van Allen EM
中科院分区：
文献类型：
--
作者：
Conway JR;Dietlein F;Taylor-Weiner A;AlDubayan S;Vokes N;Keenan T;Reardon B;He MX;Margolis CA;Weirather JL;Haq R;Schilling B;Stephen Hodi F;Schadendorf D;Liu D;Van Allen EM
我们对 1,048 种黑色素瘤进行了统一的分子和临床分析，发现亚型（BRAF、(N)RAS、NF1、三野生型）之间显着不同的全局基因组特性、次要驱动基因的亚型特异性偏好以及先前在黑色素瘤中未报告的活跃突变过程。特定亚型中显着富集的次级驱动基因反映了其他途径的优先失调，例如 BRAF 黑色素瘤中 TGF-β 信号传导的诱导和 (N)RAS 黑色素瘤中 SWI/SNF 复合物的失活，以及选择共突变模式协调对免疫检查点阻断的选择性反应。我们还定义了三重野生型黑色素瘤的突变格局，并确定了该亚型中 DNA 修复缺陷特征的富集，这些特征与关键 DNA 修复基因的转录下调相关，并可能复兴以前被丢弃或目前未考虑的基因组分层黑色素瘤患者亚型的治疗方式。广泛而言，黑色素瘤全外显子组的统一荟萃分析确定了不同的分子驱动因素，这可能为生物学和治疗研究提供多种机会。
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), 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 TGF-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 Triple Wild-Type melanomas and identified 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 identified distinct molecular drivers that may point to multiple opportunities for biological and therapeutic investigation.
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影响因子：
19
作者：
Ceccaldi R;Rondinelli B;D'Andrea AD
通讯作者：
D'Andrea AD
影响因子：
29.4
作者：
Boland CR;Goel A
通讯作者：
Goel A
影响因子：
14.9
作者：
Bakr A;Oing C;Köcher S;Borgmann K;Dornreiter I;Petersen C;Dikomey E;Mansour WY
通讯作者：
Mansour WY
影响因子：
28.2
作者：
Birkbak NJ;Wang ZC;Kim JY;Eklund AC;Li Q;Tian R;Bowman-Colin C;Li Y;Greene-Colozzi A;Iglehart JD;Tung N;Ryan PD;Garber JE;Silver DP;Szallasi Z;Richardson AL
通讯作者：
Richardson AL
影响因子：
6.6
作者：
Cirenajwis H;Lauss M;Ekedahl H;Törngren T;Kvist A;Saal LH;Olsson H;Staaf J;Carneiro A;Ingvar C;Harbst K;Hayward NK;Jönsson G
通讯作者：
Jönsson G