Work

Whole genome sequencing and the genetics of extramedullary disease in multiple myeloma

Year: 2025

Type: article

Abstract: Extramedullary disease (EMD) in multiple myeloma (MM) affects up to 20% of patients throughout the disease course [ 1 ]. It is associated with poor outcomes due to aggressive disease kinetics and therapy resistance, but the biology remains relatively unknown [ 2 , 3 ]. EMD is variably defined, but two major subtypes exist: extraosseous EMD arising from bone and extending into surrounding tissue, and true EMD arising by haematogenous spread, which is associated with the worst outcomes [ 2 , 3 ]. To describe the genetic landscape of haematogenous-spread EMD, we performed whole genome sequencing of extramedullary tumours from 15 patients; three patients had multiple biopsies. Patient samples were collected after written consent was obtained. Tumour DNA was obtained from two cohorts: fresh biopsies ( n = 8; QIAGEN DNeasy Blood & Tissue Kit) and formalin-fixed, paraffin-embedded (FFPE) historical samples ( n = 8; Roche High Pure FFPET DNA isolation Kit). Germline DNA was obtained from buccal swabs or stored autologous stem cells. Library preparation was optimised for DNA from FFPE samples using IDT® xGen PRISM DNA library preparation kit. Sequencing was performed on an Illumina NovaSeq® by the Australian Genome Research Facility. Briefly, bioinformatics utilised BWA-MEM, the GATK Mutect2, CNVpytor, Manta, Accucopy, SigProfilerMatrixGenerator, mmSig and FFPEsig. Liquid biopsy of circulating tumour DNA (ctDNA) utilised QX200 droplet digital PCR system (Bio-Rad®). See supplementary material for detailed methods.

Source: Blood Cancer Journal

DOI: 10.1038/s41408-024-01208-2