PhD Scientific Days 2022

Budapest, 6-7 July 2022

Pathology and Oncology I. (Poster discussion will take place in the Aula during the Coffee Break)

A Proteomic View on Somatic Mutations in Cutaneous Malignant Melanoma

Beáta Szeitz1, Nicole Woldmar2,3, Zoltán G. Páhi4,5, Fábio C.S. Nogueira6,7, A. Marcell Szász1, Lazaro H. Betancourt8, Peter L. Horvatovich9, György Marko-Varga2
1 Division of Oncology, Department of Internal Medicine and Oncology, Semmelweis University, Budapest, Hungary
2 Division of Clinical Protein Science & Imaging, Department of Clinical Sciences (Lund) and Department of Biomedical Engineering, Lund University, Lund, Sweden
3 Laboratory of Molecular Biology and Proteomics of Blood/LADETEC, Institute of Chemistry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
4 Institute of Pathology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
5 Centre of Excellence for Interdisciplinary Research, Development and Innovation, University of Szeged, Szeged, Hungary
6 Laboratory of Proteomics/LADETEC, Institute of Chemistry, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
7 Proteomics Unit, Institute of Chemistry, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
8 Section for Clinical Chemistry, Department of Translational Medicine, Lund University, Skåne University Hospital Malmö, Malmö, Sweden
9 Department of Analytical Biochemistry, Faculty of Science and Engineering, University of Groningen, Groningen, The Netherlands

Text of the abstract

Introduction: Investigations of the melanoma genome highlighted its exceptionally high somatic mutation frequencies. Next to the known genomic alterations such as BRAF, NRAS, or KIT mutations, a wide array of genes and pathways are functionally affected, which alterations may carry potential prognostic and therapeutic relevance.
Aims: We aim to systematically examine the proteome of melanoma samples to detect single amino acid variants (SAAVs) and dysregulated biological processes which might be characteristic of distinct patient cohorts.
Method: We selected previously acquired shotgun mass spectrometry-based proteomics data sets [1-3] for our investigations (240 primary/metastasis samples corresponding to 202 individual tumors). We appended the reference (SwissProt) protein sequence database with more than 520,000 melanoma-related SAAVs from the COSMIC database and reprocessed the proteomic data using Philosopher and MSFragger. The presence of the altered amino acid in the peptides’ sequence was verified in the peptide fragmentation spectra via the SpectrumAI tool.
Results: In sum, 403 SAAVs from 326 genes were identified. Each sample contained 12.6 SAAVs on average, and only 5% of the variants were shared across more than 10% of the tumors. Among the mutated proteins, members of the extracellular matrix organization, glycolysis, and various cell signaling pathways were significantly overrepresented.
Conclusion: We developed a data processing workflow that enables us to explore the mutated proteins in melanoma. Our initial results confirm the genetically known pronounced mutational heterogeneity - responsible for neoantigen generation - in melanoma and the agreement in the altered pathways across the tumors.
Funding: BS is a recipient of the Semmelweis 250+ Excellence PhD Scholarship (EFOP-3.6.3-VEKOP-16-2017-00009). NW was supported by the Brazilian foundation CAPES (Grants CAPES 88887.130697). ZGP was supported by GINOP-2.2.1-15-2017-00052 and NKFI-FK 132080. PLH was supported by the Netherlands X-omics Initiative (NWO, project 184.034.019). FCSN is supported by the Brazilian foundations CNPq (315167/2020-3) and FAPERJ (E-26/201.249/2022 and E-26/211.306/2021).
1. L.H. Betancourt et al., Clin Transl Med 11(7), e451 (2021).
2. L.H. Betancourt et al., Clin Transl Med 11(7), e473 (2021).
3. L. Szadai et al., Cancers 13(23), 6105 (2021).