Background: Melanoma is a highly heterogeneous disease, and a deeper molecular classification is essential for improving patient stratification and treatment approaches. Here, we describe the histopathology-driven proteogenomic landscape of 142 treatment-naïve metastatic melanoma samples to uncover molecular subtypes and clinically relevant biomarkers. Methods: We performed an integrative proteogenomic analysis to identify proteomic subtypes, assess the impact of BRAF V600 mutations, and study the molecular profiles and cellular composition of the tumor microenvironment. Clinical and histopathological data were used to support findings related to tissue morphology, disease progression, and patient outcomes. Results: Our analysis revealed five distinct proteomic subtypes that integrate immune and stromal microenvironment components and correlate with clinical and histopathological parameters. We demonstrated that BRAF V600-mutated melanomas exhibit biological heterogeneity, where an oncogene-induced senescence-like phenotype is associated with improved survival. This led to a proposed mortality risk-based stratification that may contribute to more personalized treatment strategies. Furthermore, tumor microenvironment composition strongly correlated with disease progression and patient outcomes, highlighting a histopathological connective tissue-to-tumor ratio assessment as a potential decision-making tool. We identified a melanoma-associated SAAV signature linked to extracellular matrix remodeling and SAAV-derived neoantigens as potential targets for anti-tumor immune responses. Conclusions: This study provides a comprehensive stratification of metastatic melanoma, integrating proteogenomic insights with histopathological features. The findings may aid in the development of tailored diagnostic and therapeutic strategies, improving patient management and outcomes.
背景：黑色素瘤是一种高度异质性疾病，深入的分子分型对于改善患者分层和治疗策略至关重要。本研究通过组织病理学驱动的蛋白质基因组学分析，描绘了142例初治转移性黑色素瘤样本的分子图谱，旨在揭示分子亚型及临床相关生物标志物。 方法：我们采用整合性蛋白质基因组学分析方法，识别蛋白质组学亚型，评估BRAF V600突变的影响，并研究肿瘤微环境的分子特征及细胞组成。临床与组织病理学数据用于支持与组织形态、疾病进展及患者预后相关的发现。 结果：分析揭示了五种不同的蛋白质组学亚型，这些亚型整合了免疫与基质微环境组分，并与临床及组织病理学参数相关。我们证实BRAF V600突变型黑色素瘤具有生物学异质性，其中癌基因诱导的衰老样表型与改善的生存期相关。基于此，我们提出了以死亡风险为基础的分层模型，可能有助于制定更个体化的治疗策略。此外，肿瘤微环境组成与疾病进展和患者预后密切相关，提示组织病理学中的结缔组织-肿瘤比率评估可作为潜在的临床决策工具。我们鉴定出与细胞外基质重塑相关的黑色素瘤特异性氨基酸变异特征，并发现其衍生的新抗原可能成为抗肿瘤免疫反应的潜在靶点。 结论：本研究通过整合蛋白质基因组学特征与组织病理学特点，提供了转移性黑色素瘤的全面分层框架。这些发现可能有助于开发个体化的诊断与治疗策略，从而改善患者管理和临床预后。
Proteogenomic Profiling of Treatment-Naïve Metastatic Malignant Melanoma
肿瘤(癌症)患者之家