黑色素瘤是最常见的皮肤癌之一，具有高转移率和不良预后。了解其分子发病机制对于改进其诊断和治疗至关重要。对 207 例初治黑色素瘤（原发性皮肤黑色素瘤 (CM, n = 28)、原发性肢端黑色素瘤 (AM, n = 81)、原发性粘膜黑色素瘤 (MM, n = 28)、转移性黑色素瘤 (n = 27) 和痣 (n = 43)) 提供了对黑色素瘤生物学的见解。多变量分析表明 PRKDC 扩增是黑色素瘤的预后分子。进一步的蛋白质组学分析结合功能实验表明，PRKDC扩增的顺式效应可能通过激活DNA修复和叶酸代谢途径导致肿瘤增殖。基于蛋白质组的原发性黑色素瘤分层定义了三种与预后相关的亚型，即ECM亚型、血管生成亚型（具有高转移率）和细胞增殖亚型，这为特定黑色素瘤的特异性靶向治疗的利用提供了重要框架亚型。免疫分类确定了三种免疫亚型。结合独立的抗 PD-1 治疗队列的进一步分析表明，MAPK7-NFKB 信号通路的上调可能促进 T 细胞募集并提高患者对免疫治疗的敏感性。相比之下，PRKDC 可能通过促进黑色素瘤细胞中的 DNA 修复来降低黑色素瘤患者对免疫治疗的敏感性。这些结果强调了多组学数据的临床价值，并有可能提高对黑色素瘤治疗的理解。© 2024。作者。

Melanoma is one of the most prevalent skin cancers, with high metastatic rates and poor prognosis. Understanding its molecular pathogenesis is crucial for improving its diagnosis and treatment. Integrated analysis of multi-omics data from 207 treatment-naïve melanomas (primary-cutaneous-melanomas (CM, n = 28), primary-acral-melanomas (AM, n = 81), primary-mucosal-melanomas (MM, n = 28), metastatic-melanomas (n = 27), and nevi (n = 43)) provides insights into melanoma biology. Multivariate analysis reveals that PRKDC amplification is a prognostic molecule for melanomas. Further proteogenomic analysis combined with functional experiments reveals that the cis-effect of PRKDC amplification may lead to tumor proliferation through the activation of DNA repair and folate metabolism pathways. Proteome-based stratification of primary melanomas defines three prognosis-related subtypes, namely, the ECM subtype, angiogenesis subtype (with a high metastasis rate), and cell proliferation subtype, which provides an essential framework for the utilization of specific targeted therapies for particular melanoma subtypes. The immune classification identifies three immune subtypes. Further analysis combined with an independent anti-PD-1 treatment cohort reveals that upregulation of the MAPK7-NFKB signaling pathway may facilitate T-cell recruitment and increase the sensitivity of patients to immunotherapy. In contrast, PRKDC may reduce the sensitivity of melanoma patients to immunotherapy by promoting DNA repair in melanoma cells. These results emphasize the clinical value of multi-omics data and have the potential to improve the understanding of melanoma treatment.© 2024. The Author(s).