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

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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 languageEnglish
Pages (from-to)1887-1897
Number of pages11
JournalLeukemia
Volume36
Issue number7
Early online date28 May 2022
DOIs
Publication statusPublished - 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).

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