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Proteogenomic Profiling of Treatment-Naïve Metastatic Malignant Melanoma

Kuras, Magdalena LU orcid ; Betancourt, Lazaro Hiram LU ; Hong, Runyu ; Szadai, Leticia ; Rodriguez, Jimmy ; Horvatovich, Peter LU ; Pla, Indira LU orcid ; Eriksson, Jonatan LU ; Szeitz, Beáta and Deszcz, Bartłomiej , et al. (2025) In Cancers 17(5). p.1-35
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Cancers
volume
17
issue
5
article number
832
pages
1 - 35
publisher
MDPI AG
external identifiers
  • pmid:40075679
  • scopus:86000539072
ISSN
2072-6694
DOI
10.3390/cancers17050832
language
English
LU publication?
yes
id
eba61d74-6249-49ed-8206-ccd7e1a2e814
date added to LUP
2025-04-10 22:35:09
date last changed
2025-06-06 07:58:32
@article{eba61d74-6249-49ed-8206-ccd7e1a2e814,
  abstract     = {{<p>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.</p><p>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.</p><p>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.</p><p>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.</p>}},
  author       = {{Kuras, Magdalena and Betancourt, Lazaro Hiram and Hong, Runyu and Szadai, Leticia and Rodriguez, Jimmy and Horvatovich, Peter and Pla, Indira and Eriksson, Jonatan and Szeitz, Beáta and Deszcz, Bartłomiej and Welinder, Charlotte and Sugihara, Yutaka and Ekedahl, Henrik and Baldetorp, Bo and Ingvar, Christian and Lundgren, Lotta and Lindberg, Henrik and Oskolas, Henriett and Horvath, Zsolt and Rezeli, Melinda and Gil, Jeovanis and Appelqvist, Roger and Kemény, Lajos V and Malm, Johan and Sanchez, Aniel and Szasz, Attila Marcell and Pawłowski, Krzysztof and Wieslander, Elisabet and Fenyö, David and Nemeth, Istvan Balazs and Marko-Varga, György}},
  issn         = {{2072-6694}},
  language     = {{eng}},
  month        = {{02}},
  number       = {{5}},
  pages        = {{1--35}},
  publisher    = {{MDPI AG}},
  series       = {{Cancers}},
  title        = {{Proteogenomic Profiling of Treatment-Naïve Metastatic Malignant Melanoma}},
  url          = {{http://dx.doi.org/10.3390/cancers17050832}},
  doi          = {{10.3390/cancers17050832}},
  volume       = {{17}},
  year         = {{2025}},
}