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Comprehensive genomic analysis of refractory multiple myeloma reveals a complex mutational landscape associated with drug resistance and novel therapeutic vulnerabilities
The outcomes of patients with multiple myeloma (MM) refractory to immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs) remain poor. In this study, we performed whole genome and transcriptome sequencing of 39 heavily pretreated relapsed/refractory MM (RRMM) patients to identify mechanisms...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Fondazione Ferrata Storti
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9335090/ https://www.ncbi.nlm.nih.gov/pubmed/35045690 http://dx.doi.org/10.3324/haematol.2021.279360 |
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author | Giesen, Nicola Paramasivam, Nagarajan Toprak, Umut H. Huebschmann, Daniel Xu, Jing Uhrig, Sebastian Samur, Mehmet Bähr, Stella Fröhlich, Martina Mughal, Sadaf S. Mai, Elias K. Jauch, Anna Müller-Tidow, Carsten Brors, Benedikt Munshi, Nikhil Goldschmidt, Hartmut Weinhold, Niels Schlesner, Matthias Raab, Marc S. |
author_facet | Giesen, Nicola Paramasivam, Nagarajan Toprak, Umut H. Huebschmann, Daniel Xu, Jing Uhrig, Sebastian Samur, Mehmet Bähr, Stella Fröhlich, Martina Mughal, Sadaf S. Mai, Elias K. Jauch, Anna Müller-Tidow, Carsten Brors, Benedikt Munshi, Nikhil Goldschmidt, Hartmut Weinhold, Niels Schlesner, Matthias Raab, Marc S. |
author_sort | Giesen, Nicola |
collection | PubMed |
description | The outcomes of patients with multiple myeloma (MM) refractory to immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs) remain poor. In this study, we performed whole genome and transcriptome sequencing of 39 heavily pretreated relapsed/refractory MM (RRMM) patients to identify mechanisms of resistance and potential therapeutic targets. We observed a high mutational load and indications of increased genomic instability. Recurrently mutated genes in RRMM, which had not been previously reported or only observed at a lower frequency in newly diagnosed MM, included NRAS, BRAF, TP53, SLC4A7, MLLT4, EWSR1, HCFC2, and COPS3. We found multiple genomic regions with bi-allelic events affecting tumor suppressor genes and demonstrated a significant adverse impact of bi-allelic TP53 alterations on survival. With regard to potentially resistance conferring mutations, recurrently mutated gene networks included genes with relevance for PI and IMiD activity; the latter particularly affecting members of the Cereblon and the COP9 signalosome complex. We observed a major impact of signatures associated with exposure to melphalan or impaired DNA double-strand break homologous recombination repair in RRMM. The latter coincided with mutations in genes associated with PARP inhibitor sensitivity in 49% of RRMM patients; a finding with potential therapeutic implications. In conclusion, this comprehensive genomic characterization revealed a complex mutational and structural landscape in RRMM and highlights potential implications for therapeutic strategies. |
format | Online Article Text |
id | pubmed-9335090 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Fondazione Ferrata Storti |
record_format | MEDLINE/PubMed |
spelling | pubmed-93350902022-08-26 Comprehensive genomic analysis of refractory multiple myeloma reveals a complex mutational landscape associated with drug resistance and novel therapeutic vulnerabilities Giesen, Nicola Paramasivam, Nagarajan Toprak, Umut H. Huebschmann, Daniel Xu, Jing Uhrig, Sebastian Samur, Mehmet Bähr, Stella Fröhlich, Martina Mughal, Sadaf S. Mai, Elias K. Jauch, Anna Müller-Tidow, Carsten Brors, Benedikt Munshi, Nikhil Goldschmidt, Hartmut Weinhold, Niels Schlesner, Matthias Raab, Marc S. Haematologica Article - Plasma Cell Disorders The outcomes of patients with multiple myeloma (MM) refractory to immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs) remain poor. In this study, we performed whole genome and transcriptome sequencing of 39 heavily pretreated relapsed/refractory MM (RRMM) patients to identify mechanisms of resistance and potential therapeutic targets. We observed a high mutational load and indications of increased genomic instability. Recurrently mutated genes in RRMM, which had not been previously reported or only observed at a lower frequency in newly diagnosed MM, included NRAS, BRAF, TP53, SLC4A7, MLLT4, EWSR1, HCFC2, and COPS3. We found multiple genomic regions with bi-allelic events affecting tumor suppressor genes and demonstrated a significant adverse impact of bi-allelic TP53 alterations on survival. With regard to potentially resistance conferring mutations, recurrently mutated gene networks included genes with relevance for PI and IMiD activity; the latter particularly affecting members of the Cereblon and the COP9 signalosome complex. We observed a major impact of signatures associated with exposure to melphalan or impaired DNA double-strand break homologous recombination repair in RRMM. The latter coincided with mutations in genes associated with PARP inhibitor sensitivity in 49% of RRMM patients; a finding with potential therapeutic implications. In conclusion, this comprehensive genomic characterization revealed a complex mutational and structural landscape in RRMM and highlights potential implications for therapeutic strategies. Fondazione Ferrata Storti 2022-01-20 /pmc/articles/PMC9335090/ /pubmed/35045690 http://dx.doi.org/10.3324/haematol.2021.279360 Text en Copyright© 2022 Ferrata Storti Foundation https://creativecommons.org/licenses/by-nc/4.0/This article is distributed under the terms of the Creative Commons Attribution Noncommercial License (by-nc 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. |
spellingShingle | Article - Plasma Cell Disorders Giesen, Nicola Paramasivam, Nagarajan Toprak, Umut H. Huebschmann, Daniel Xu, Jing Uhrig, Sebastian Samur, Mehmet Bähr, Stella Fröhlich, Martina Mughal, Sadaf S. Mai, Elias K. Jauch, Anna Müller-Tidow, Carsten Brors, Benedikt Munshi, Nikhil Goldschmidt, Hartmut Weinhold, Niels Schlesner, Matthias Raab, Marc S. Comprehensive genomic analysis of refractory multiple myeloma reveals a complex mutational landscape associated with drug resistance and novel therapeutic vulnerabilities |
title | Comprehensive genomic analysis of refractory multiple myeloma reveals a complex mutational landscape associated with drug resistance and novel therapeutic vulnerabilities |
title_full | Comprehensive genomic analysis of refractory multiple myeloma reveals a complex mutational landscape associated with drug resistance and novel therapeutic vulnerabilities |
title_fullStr | Comprehensive genomic analysis of refractory multiple myeloma reveals a complex mutational landscape associated with drug resistance and novel therapeutic vulnerabilities |
title_full_unstemmed | Comprehensive genomic analysis of refractory multiple myeloma reveals a complex mutational landscape associated with drug resistance and novel therapeutic vulnerabilities |
title_short | Comprehensive genomic analysis of refractory multiple myeloma reveals a complex mutational landscape associated with drug resistance and novel therapeutic vulnerabilities |
title_sort | comprehensive genomic analysis of refractory multiple myeloma reveals a complex mutational landscape associated with drug resistance and novel therapeutic vulnerabilities |
topic | Article - Plasma Cell Disorders |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9335090/ https://www.ncbi.nlm.nih.gov/pubmed/35045690 http://dx.doi.org/10.3324/haematol.2021.279360 |
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