Individualized Proteogenomics Reveals the Mutational Landscape of Melanoma Patients in Response to Immunotherapy

Immune checkpoint inhibitors are used to restore or augment antitumor immune responses and show great promise in the treatment of melanoma and other types of cancers. However, only a small percentage of patients are fully responsive to immune checkpoint inhibition, mostly due to tumor heterogeneity...

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Autores principales:	Marisa Schmitt, Tobias Sinnberg, Heike Niessner, Andrea Forschner, Claus Garbe, Boris Macek, Nicolas C. Nalpas
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	proteogenomics melanoma mass spectrometry immunotherapy whole exome sequencing Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/91ad1cf1ba114fcb9bb863931ff9ce55
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spelling	oai:doaj.org-article:91ad1cf1ba114fcb9bb863931ff9ce552021-11-11T15:30:36ZIndividualized Proteogenomics Reveals the Mutational Landscape of Melanoma Patients in Response to Immunotherapy10.3390/cancers132154112072-6694https://doaj.org/article/91ad1cf1ba114fcb9bb863931ff9ce552021-10-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/21/5411https://doaj.org/toc/2072-6694Immune checkpoint inhibitors are used to restore or augment antitumor immune responses and show great promise in the treatment of melanoma and other types of cancers. However, only a small percentage of patients are fully responsive to immune checkpoint inhibition, mostly due to tumor heterogeneity and primary resistance to therapy. Both of these features are largely driven by the accumulation of patient-specific mutations, pointing to the need for personalized approaches in diagnostics and immunotherapy. Proteogenomics integrates patient-specific genomic and proteomic data to study cancer development, tumor heterogeneity and resistance mechanisms. Using this approach, we characterized the mutational landscape of four clinical melanoma patients. This enabled the quantification of hundreds of sample-specific amino acid variants, among them many that were previously not reported in melanoma. Changes in abundance at the protein and phosphorylation site levels revealed patient-specific over-represented pathways, notably linked to melanoma development (MAPK1 activation) or immunotherapy (NLRP1 inflammasome). Personalized data integration resulted in the prediction of protein drug targets, such as the drugs vandetanib and bosutinib, which were experimentally validated and led to a reduction in the viability of tumor cells. Our study emphasizes the potential of proteogenomic approaches to study personalized mutational landscapes, signaling networks and therapy options.Marisa SchmittTobias SinnbergHeike NiessnerAndrea ForschnerClaus GarbeBoris MacekNicolas C. NalpasMDPI AGarticleproteogenomicsmelanomamass spectrometryimmunotherapywhole exome sequencingNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5411, p 5411 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	proteogenomics melanoma mass spectrometry immunotherapy whole exome sequencing Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	proteogenomics melanoma mass spectrometry immunotherapy whole exome sequencing Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Marisa Schmitt Tobias Sinnberg Heike Niessner Andrea Forschner Claus Garbe Boris Macek Nicolas C. Nalpas Individualized Proteogenomics Reveals the Mutational Landscape of Melanoma Patients in Response to Immunotherapy
description	Immune checkpoint inhibitors are used to restore or augment antitumor immune responses and show great promise in the treatment of melanoma and other types of cancers. However, only a small percentage of patients are fully responsive to immune checkpoint inhibition, mostly due to tumor heterogeneity and primary resistance to therapy. Both of these features are largely driven by the accumulation of patient-specific mutations, pointing to the need for personalized approaches in diagnostics and immunotherapy. Proteogenomics integrates patient-specific genomic and proteomic data to study cancer development, tumor heterogeneity and resistance mechanisms. Using this approach, we characterized the mutational landscape of four clinical melanoma patients. This enabled the quantification of hundreds of sample-specific amino acid variants, among them many that were previously not reported in melanoma. Changes in abundance at the protein and phosphorylation site levels revealed patient-specific over-represented pathways, notably linked to melanoma development (MAPK1 activation) or immunotherapy (NLRP1 inflammasome). Personalized data integration resulted in the prediction of protein drug targets, such as the drugs vandetanib and bosutinib, which were experimentally validated and led to a reduction in the viability of tumor cells. Our study emphasizes the potential of proteogenomic approaches to study personalized mutational landscapes, signaling networks and therapy options.
format	article
author	Marisa Schmitt Tobias Sinnberg Heike Niessner Andrea Forschner Claus Garbe Boris Macek Nicolas C. Nalpas
author_facet	Marisa Schmitt Tobias Sinnberg Heike Niessner Andrea Forschner Claus Garbe Boris Macek Nicolas C. Nalpas
author_sort	Marisa Schmitt
title	Individualized Proteogenomics Reveals the Mutational Landscape of Melanoma Patients in Response to Immunotherapy
title_short	Individualized Proteogenomics Reveals the Mutational Landscape of Melanoma Patients in Response to Immunotherapy
title_full	Individualized Proteogenomics Reveals the Mutational Landscape of Melanoma Patients in Response to Immunotherapy
title_fullStr	Individualized Proteogenomics Reveals the Mutational Landscape of Melanoma Patients in Response to Immunotherapy
title_full_unstemmed	Individualized Proteogenomics Reveals the Mutational Landscape of Melanoma Patients in Response to Immunotherapy
title_sort	individualized proteogenomics reveals the mutational landscape of melanoma patients in response to immunotherapy
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/91ad1cf1ba114fcb9bb863931ff9ce55
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Individualized Proteogenomics Reveals the Mutational Landscape of Melanoma Patients in Response to Immunotherapy

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