Abstract 5019: Genomic landscape, tumor heterogeneity and immune-related post-translational regulation in cutaneous melanoma

Melanoma, the deadliest form of skin cancer, accounts for an estimated 100,640 new diagnoses and 8290 deaths in the United States in 2024. This study leverages 13 multi-omics data types from 164 melanoma samples provided by the Clinical Proteomic Tumor Analysis Consortium (CPTAC), uniquely featuring ubiquitinome and HLA peptidome profiling, to investigate the genomic aberrations, molecular subtypes, tumor microenvironment heterogeneity and post-translational modifications (PTMs).Key findings include mutual exclusivity between hotspot mutations affecting the kinase activity of BRAF and RAS, as well as between alteration types impacting TERT expression. High ultraviolet (UV) impact melanoma is characterized by NF1 loss and TERT promoter mutations. Metastatic melanoma shows higher whole genome duplication (WGD) prevalence (58% vs 46%), with early focal loss of CDKN2A and PTEN preceding WGD. A chr5-12 translocation involving CDK4 and TERT and significant clonal heterogeneity were identified, with single-clone tumors linked to better prognosis (p = 0.029). Transcriptional states derived from single-cell RNA sequencing (melanocytic, transitory, invasive) and proteome clustering based on immune checkpoint inhibitor (ICI) features highlight immune response as a key determinant of melanoma heterogeneity. HLA peptidome analysis identified 830 tumor antigen candidates, including 23 non-coding antigens shared across >6 patients, predominantly sourced from introns and MAGEA family genes. Metabolomic and lipidomic data provide insights into immune-metabolic interactions, while ubiquitinome and acetylome profiling are being further investigated to understand immune differences in melanoma. These findings underscore the critical role of post-translational regulation and immune regulation in melanoma progression and therapeutic targeting. Citation Format: Jianhui Gong, Gabriel Cruz, Yamei Deng, Maria Virginia Ruiz Cuevas, Chandan Kumar-Sinha, Rahul Mannan, Yi Hsiao, Francesca Petralia, Weiping Ma, Shrabanti Chowdhury, Noshad Hosseini, CPTAC Clinical Proteomic Tumor Analysis Consortium, Gilbert Omenn, Arul Chinnaiyan, Paul Harms, Raghav Jain, Jennifer Kyle, Avi Ma'ayan, Saravana Dhanasekaran, Karl Clauser, Hui Zhang, Alexey Nesvizhskii, Steven Carr, Tao Liu, Pei Wang, Marcin Cieslik. Genomic landscape, tumor heterogeneity and immune-related post-translational regulation in cutaneous melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5019.