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.

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、三重野生型（TWT））、亚型特异性偏好的次要驱动基因和活跃的突变过程之间存在显着不同的全局基因组特性以前在黑色素瘤中未报道。在特定亚型中显着富集的二级驱动基因反映了其他途径的优先失调，例如在BRAF黑色素瘤中诱导转化生长因子-β 信号传导和(N)RAS 中SWI/SNF 复合物的失活黑色素瘤和选择的共突变模式协调对免疫检查点封锁的选择性反应。我们还定义了 TWT 黑色素瘤的突变情况，并揭示了该亚型中 DNA 修复缺陷特征的富集，这与关键 DNA 修复基因的转录下调有关，并且可能会恢复以前被丢弃或目前未考虑的基因组分层黑色素瘤的治疗方式患者子集。从广义上讲，对黑色素瘤全外显子组的统一荟萃分析揭示了不同的分子驱动因素，可能指向生物学和治疗研究的多种机会。