Proteogenomic Profiling of Treatment-Naïve Metastatic Malignant Melanoma

Magdalena Kuras; Lazaro Hiram Betancourt; Runyu Hong; Leticia Szadai; Jimmy Rodriguez; Peter Horvatovich; Indira Pla; Jonatan Eriksson; Beáta Szeitz; Bartłomiej Deszcz; Charlotte Welinder; Yutaka Sugihara; Henrik Ekedahl; Bo Baldetorp; Christian Ingvar; Lotta Lundgren; Henrik Lindberg; Henriett Oskolas; Zsolt Horvath; Melinda Rezeli; Jeovanis Gil; Roger Appelqvist; Lajos V Kemény; Johan Malm; Aniel Sanchez; Attila Marcell Szasz; Krzysztof Pawłowski; Elisabet Wieslander; David Fenyö; Istvan Balazs Nemeth; György Marko-Varga

doi:10.3390/cancers17050832

Proteogenomic Profiling of Treatment-Naïve Metastatic Malignant Melanoma

Cancers (Basel). 2025 Feb 27;17(5):832. doi: 10.3390/cancers17050832.

Authors

Magdalena Kuras^{1

2}, Lazaro Hiram Betancourt^{1

3}, Runyu Hong^{4

5}, Leticia Szadai⁶, Jimmy Rodriguez⁷, Peter Horvatovich^{2

8}, Indira Pla², Jonatan Eriksson², Beáta Szeitz⁹, Bartłomiej Deszcz¹⁰, Charlotte Welinder³, Yutaka Sugihara², Henrik Ekedahl^{3

11}, Bo Baldetorp³, Christian Ingvar^{11

12}, Lotta Lundgren^{3

11}, Henrik Lindberg², Henriett Oskolas³, Zsolt Horvath², Melinda Rezeli², Jeovanis Gil¹, Roger Appelqvist², Lajos V Kemény^{13

14

15

16}, Johan Malm¹, Aniel Sanchez¹, Attila Marcell Szasz¹⁷, Krzysztof Pawłowski^{1

10

18}, Elisabet Wieslander¹, David Fenyö^{4

5}, Istvan Balazs Nemeth⁶, György Marko-Varga^{2

19

20}

Affiliations

¹ Department of Translational Medicine, Lund University, Skåne University Hospital Malmö, 214 28 Malmö, Sweden.
² Department of Biomedical Engineering, Lund University, 221 00 Lund, Sweden.
³ Department of Clinical Sciences Lund, Division of Oncology, Lund University, 221 00 Lund, Sweden.
⁴ Institute for Systems Genetics, NYU Grossman School of Medicine, New York, NY 10016, USA.
⁵ Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA.
⁶ Department of Dermatology and Allergology, University of Szeged, 6720 Szeged, Hungary.
⁷ Department of Biochemistry and Biophysics, Karolinska Institute, 171 77 Stockholm, Sweden.
⁸ Department of Analytical Biochemistry, Faculty of Science and Engineering, University of Groningen, 9712 CP Groningen, The Netherlands.
⁹ Division of Oncology, Department of Internal Medicine and Oncology, Semmelweis University, 1085 Budapest, Hungary.
¹⁰ Department of Biochemistry and Microbiology, Warsaw University of Life Sciences, 02-787 Warsaw, Poland.
¹¹ SUS University Hospital Lund, 222 42 Lund, Sweden.
¹² Department of Surgery, Clinical Sciences, Lund University, SUS, 221 00 Lund, Sweden.
¹³ HCEMM-SU Translational Dermatology Research Group, Semmelweis University, 1085 Budapest, Hungary.
¹⁴ Department of Dermatology, Venereology and Dermatooncology, Faculty of Medicine, Semmelweis University, 1085 Budapest, Hungary.
¹⁵ Department of Physiology, Faculty of Medicine, Semmelweis University, 1085 Budapest, Hungary.
¹⁶ MTA-SE Lendület "Momentum" Dermatology Research Group, Hungarian Academy of Sciences and Semmelweis University, 1085 Budapest, Hungary.
¹⁷ Department of Bioinformatics, Semmelweis University, 1085 Budapest, Hungary.
¹⁸ Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
¹⁹ Chemical Genomics Global Research Lab, Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea.
²⁰ 1st Department of Surgery, Tokyo Medical University, Tokyo 160-8402, Japan.

Abstract

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.

Keywords: BRAF V600E; histopathology; lymph node metastases; melanoma; proteogenomics; proteomics; single amino acid variants; stratification; subtypes; tumor microenvironment.

Abstract

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