Clonal evolution after treatment pressure in multiple myeloma: heterogenous genomic aberrations and transcriptomic convergence

Kristine Misund; Davine Hofste op Bruinink; Eivind Coward; Remco M. Hoogenboezem; Even Holth Rustad; Mathijs A. Sanders; Morten Rye; Anne Marit Sponaas; Bronno van der Holt; Sonja Zweegman; Eivind Hovig; Leonardo A. Meza-Zepeda; Anders Sundan; Ola Myklebost; Pieter Sonneveld; Anders Waage

doi:10.1038/s41375-022-01597-y

Clonal evolution after treatment pressure in multiple myeloma: heterogenous genomic aberrations and transcriptomic convergence

Kristine Misund^*, Davine Hofste op Bruinink, Eivind Coward, Remco M. Hoogenboezem, Even Holth Rustad, Mathijs A. Sanders, Morten Rye, Anne Marit Sponaas, Bronno van der Holt, Sonja Zweegman, Eivind Hovig, Leonardo A. Meza-Zepeda, Anders Sundan, Ola Myklebost, Pieter Sonneveld, Anders Waage

^*Corresponding author for this work

Hematology

Research output: Contribution to journal › Article › Academic › peer-review

41 Citations (Scopus)

41 Downloads (Pure)

Abstract

We investigated genomic and transcriptomic changes in paired tumor samples of 29 in-house multiple myeloma (MM) patients and 28 patients from the MMRF CoMMpass study before and after treatment. A change in clonal composition was found in 46/57 (82%) of patients, and single-nucleotide variants (SNVs) increased from median 67 to 86. The highest increase in prevalence of genetic aberrations was found in RAS genes (60% to 72%), amp1q21 (18% to 35%), and TP53 (9% to 18%). The SBS-MM1 mutation signature was detected both in patients receiving high and low dose melphalan. A total of 2589 genes were differentially expressed between early and late samples (FDR < 0.05). Gene set enrichment analysis (GSEA) showed increased expression of E2F, MYC, and glycolysis pathways and a decreased expression in TNF-NFkB and TGFbeta pathways in late compared to early stage. Single sample GSEA (ssGSEA) scores of differentially expressed pathways revealed that these changes were most evident in end-stage disease. Increased expression of several potentially targetable genes was found at late disease stages, including cancer-testis antigens, XPO1 and ABC transporters. Our study demonstrates a transcriptomic convergence of pathways supporting increased proliferation and metabolism during disease progression in MM.

Original language	English
Pages (from-to)	1887-1897
Number of pages	11
Journal	Leukemia
Volume	36
Issue number	7
Early online date	28 May 2022
DOIs	https://doi.org/10.1038/s41375-022-01597-y
Publication status	Published - Jul 2022

Bibliographical note

Funding Information:
The authors appreciate the valuable advice and practical assistance provided by Biobank1®, the research biobank of Central Norway. The WES and RNA-seq was provided by the Genomics Core Facility (GCF), Norwegian University of Science and Technology (NTNU). GCF is funded by the Faculty of Medicine and Health Sciences at NTNU and Central Norway Regional Health Authority. Thanks to the Multiple Myeloma Research Foundation (MMRF) for providing the CoMMpass dataset. The study is funded from the Norwegian Research Council, the Liaison Committee between the Central Norway Regional Health Authority and NTNU, and the Dutch Cancer Foundation. The study was conducted as a part of the Norwegian Cancer Genomics Consortium.

Funding Information:
The authors appreciate the valuable advice and practical assistance provided by Biobank1®, the research biobank of Central Norway. The WES and RNA-seq was provided by the Genomics Core Facility (GCF), Norwegian University of Science and Technology (NTNU). GCF is funded by the Faculty of Medicine and Health Sciences at NTNU and Central Norway Regional Health Authority. Thanks to the Multiple Myeloma Research Foundation (MMRF) for providing the CoMMpass dataset. The study is funded from the Norwegian Research Council, the Liaison Committee between the Central Norway Regional Health Authority and NTNU, and the Dutch Cancer Foundation. The study was conducted as a part of the Norwegian Cancer Genomics Consortium.

Publisher Copyright:
© 2022, The Author(s).

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41375-022-01597-yLicence: CC BY

Clonal evolution after treatment pressure in multiple myelomaFinal published version, 1.85 MBLicence: CC BY

Cite this

Misund, K., Hofste op Bruinink, D., Coward, E., Hoogenboezem, R. M., Rustad, E. H., Sanders, M. A., Rye, M., Sponaas, A. M., van der Holt, B., Zweegman, S., Hovig, E., Meza-Zepeda, L. A., Sundan, A., Myklebost, O., Sonneveld, P., & Waage, A. (2022). Clonal evolution after treatment pressure in multiple myeloma: heterogenous genomic aberrations and transcriptomic convergence. Leukemia, 36(7), 1887-1897. https://doi.org/10.1038/s41375-022-01597-y

@article{2a919cee97bc4a1499e8349c4ed4e1b8,

title = "Clonal evolution after treatment pressure in multiple myeloma: heterogenous genomic aberrations and transcriptomic convergence",

abstract = "We investigated genomic and transcriptomic changes in paired tumor samples of 29 in-house multiple myeloma (MM) patients and 28 patients from the MMRF CoMMpass study before and after treatment. A change in clonal composition was found in 46/57 (82%) of patients, and single-nucleotide variants (SNVs) increased from median 67 to 86. The highest increase in prevalence of genetic aberrations was found in RAS genes (60% to 72%), amp1q21 (18% to 35%), and TP53 (9% to 18%). The SBS-MM1 mutation signature was detected both in patients receiving high and low dose melphalan. A total of 2589 genes were differentially expressed between early and late samples (FDR < 0.05). Gene set enrichment analysis (GSEA) showed increased expression of E2F, MYC, and glycolysis pathways and a decreased expression in TNF-NFkB and TGFbeta pathways in late compared to early stage. Single sample GSEA (ssGSEA) scores of differentially expressed pathways revealed that these changes were most evident in end-stage disease. Increased expression of several potentially targetable genes was found at late disease stages, including cancer-testis antigens, XPO1 and ABC transporters. Our study demonstrates a transcriptomic convergence of pathways supporting increased proliferation and metabolism during disease progression in MM.",

author = "Kristine Misund and {Hofste op Bruinink}, Davine and Eivind Coward and Hoogenboezem, {Remco M.} and Rustad, {Even Holth} and Sanders, {Mathijs A.} and Morten Rye and Sponaas, {Anne Marit} and {van der Holt}, Bronno and Sonja Zweegman and Eivind Hovig and Meza-Zepeda, {Leonardo A.} and Anders Sundan and Ola Myklebost and Pieter Sonneveld and Anders Waage",

note = "Funding Information: The authors appreciate the valuable advice and practical assistance provided by Biobank1{\textregistered}, the research biobank of Central Norway. The WES and RNA-seq was provided by the Genomics Core Facility (GCF), Norwegian University of Science and Technology (NTNU). GCF is funded by the Faculty of Medicine and Health Sciences at NTNU and Central Norway Regional Health Authority. Thanks to the Multiple Myeloma Research Foundation (MMRF) for providing the CoMMpass dataset. The study is funded from the Norwegian Research Council, the Liaison Committee between the Central Norway Regional Health Authority and NTNU, and the Dutch Cancer Foundation. The study was conducted as a part of the Norwegian Cancer Genomics Consortium. Funding Information: The authors appreciate the valuable advice and practical assistance provided by Biobank1{\textregistered}, the research biobank of Central Norway. The WES and RNA-seq was provided by the Genomics Core Facility (GCF), Norwegian University of Science and Technology (NTNU). GCF is funded by the Faculty of Medicine and Health Sciences at NTNU and Central Norway Regional Health Authority. Thanks to the Multiple Myeloma Research Foundation (MMRF) for providing the CoMMpass dataset. The study is funded from the Norwegian Research Council, the Liaison Committee between the Central Norway Regional Health Authority and NTNU, and the Dutch Cancer Foundation. The study was conducted as a part of the Norwegian Cancer Genomics Consortium. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = jul,

doi = "10.1038/s41375-022-01597-y",

language = "English",

volume = "36",

pages = "1887--1897",

journal = "Leukemia",

issn = "0887-6924",

publisher = "Springer Nature",

number = "7",

}

Misund, K, Hofste op Bruinink, D, Coward, E, Hoogenboezem, RM, Rustad, EH, Sanders, MA, Rye, M, Sponaas, AM, van der Holt, B, Zweegman, S, Hovig, E, Meza-Zepeda, LA, Sundan, A, Myklebost, O, Sonneveld, P & Waage, A 2022, 'Clonal evolution after treatment pressure in multiple myeloma: heterogenous genomic aberrations and transcriptomic convergence', Leukemia, vol. 36, no. 7, pp. 1887-1897. https://doi.org/10.1038/s41375-022-01597-y

TY - JOUR

T1 - Clonal evolution after treatment pressure in multiple myeloma

T2 - heterogenous genomic aberrations and transcriptomic convergence

AU - Misund, Kristine

AU - Hofste op Bruinink, Davine

AU - Coward, Eivind

AU - Hoogenboezem, Remco M.

AU - Rustad, Even Holth

AU - Sanders, Mathijs A.

AU - Rye, Morten

AU - Sponaas, Anne Marit

AU - van der Holt, Bronno

AU - Zweegman, Sonja

AU - Hovig, Eivind

AU - Meza-Zepeda, Leonardo A.

AU - Sundan, Anders

AU - Myklebost, Ola

AU - Sonneveld, Pieter

AU - Waage, Anders

N1 - Funding Information: The authors appreciate the valuable advice and practical assistance provided by Biobank1®, the research biobank of Central Norway. The WES and RNA-seq was provided by the Genomics Core Facility (GCF), Norwegian University of Science and Technology (NTNU). GCF is funded by the Faculty of Medicine and Health Sciences at NTNU and Central Norway Regional Health Authority. Thanks to the Multiple Myeloma Research Foundation (MMRF) for providing the CoMMpass dataset. The study is funded from the Norwegian Research Council, the Liaison Committee between the Central Norway Regional Health Authority and NTNU, and the Dutch Cancer Foundation. The study was conducted as a part of the Norwegian Cancer Genomics Consortium. Funding Information: The authors appreciate the valuable advice and practical assistance provided by Biobank1®, the research biobank of Central Norway. The WES and RNA-seq was provided by the Genomics Core Facility (GCF), Norwegian University of Science and Technology (NTNU). GCF is funded by the Faculty of Medicine and Health Sciences at NTNU and Central Norway Regional Health Authority. Thanks to the Multiple Myeloma Research Foundation (MMRF) for providing the CoMMpass dataset. The study is funded from the Norwegian Research Council, the Liaison Committee between the Central Norway Regional Health Authority and NTNU, and the Dutch Cancer Foundation. The study was conducted as a part of the Norwegian Cancer Genomics Consortium. Publisher Copyright: © 2022, The Author(s).

PY - 2022/7

Y1 - 2022/7

N2 - We investigated genomic and transcriptomic changes in paired tumor samples of 29 in-house multiple myeloma (MM) patients and 28 patients from the MMRF CoMMpass study before and after treatment. A change in clonal composition was found in 46/57 (82%) of patients, and single-nucleotide variants (SNVs) increased from median 67 to 86. The highest increase in prevalence of genetic aberrations was found in RAS genes (60% to 72%), amp1q21 (18% to 35%), and TP53 (9% to 18%). The SBS-MM1 mutation signature was detected both in patients receiving high and low dose melphalan. A total of 2589 genes were differentially expressed between early and late samples (FDR < 0.05). Gene set enrichment analysis (GSEA) showed increased expression of E2F, MYC, and glycolysis pathways and a decreased expression in TNF-NFkB and TGFbeta pathways in late compared to early stage. Single sample GSEA (ssGSEA) scores of differentially expressed pathways revealed that these changes were most evident in end-stage disease. Increased expression of several potentially targetable genes was found at late disease stages, including cancer-testis antigens, XPO1 and ABC transporters. Our study demonstrates a transcriptomic convergence of pathways supporting increased proliferation and metabolism during disease progression in MM.

AB - We investigated genomic and transcriptomic changes in paired tumor samples of 29 in-house multiple myeloma (MM) patients and 28 patients from the MMRF CoMMpass study before and after treatment. A change in clonal composition was found in 46/57 (82%) of patients, and single-nucleotide variants (SNVs) increased from median 67 to 86. The highest increase in prevalence of genetic aberrations was found in RAS genes (60% to 72%), amp1q21 (18% to 35%), and TP53 (9% to 18%). The SBS-MM1 mutation signature was detected both in patients receiving high and low dose melphalan. A total of 2589 genes were differentially expressed between early and late samples (FDR < 0.05). Gene set enrichment analysis (GSEA) showed increased expression of E2F, MYC, and glycolysis pathways and a decreased expression in TNF-NFkB and TGFbeta pathways in late compared to early stage. Single sample GSEA (ssGSEA) scores of differentially expressed pathways revealed that these changes were most evident in end-stage disease. Increased expression of several potentially targetable genes was found at late disease stages, including cancer-testis antigens, XPO1 and ABC transporters. Our study demonstrates a transcriptomic convergence of pathways supporting increased proliferation and metabolism during disease progression in MM.

UR - http://www.scopus.com/inward/record.url?scp=85131075325&partnerID=8YFLogxK

U2 - 10.1038/s41375-022-01597-y

DO - 10.1038/s41375-022-01597-y

M3 - Article

C2 - 35643867

AN - SCOPUS:85131075325

SN - 0887-6924

VL - 36

SP - 1887

EP - 1897

JO - Leukemia

JF - Leukemia

IS - 7

ER -

Clonal evolution after treatment pressure in multiple myeloma: heterogenous genomic aberrations and transcriptomic convergence

Abstract

Bibliographical note

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this