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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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Fondazione Ferrata Storti 2022
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.
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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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