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An enhanced genetic model of relapsed IGH-translocated multiple myeloma evolutionary dynamics.

Authors :
Hoang PH
Cornish AJ
Sherborne AL
Chubb D
Kimber S
Jackson G
Morgan GJ
Cook G
Kinnersley B
Kaiser M
Houlston RS
Source :
Blood cancer journal [Blood Cancer J] 2020 Oct 14; Vol. 10 (10), pp. 101. Date of Electronic Publication: 2020 Oct 14.
Publication Year :
2020

Abstract

Most patients with multiple myeloma (MM) die from progressive disease after relapse. To advance our understanding of MM evolution mechanisms, we performed whole-genome sequencing of 80 IGH-translocated tumour-normal newly diagnosed pairs and 24 matched relapsed tumours from the Myeloma XI trial. We identify multiple events as potentially important for survival and therapy-resistance at relapse including driver point mutations (e.g., TET2), translocations (MAP3K14), lengthened telomeres, and increased genomic instability (e.g., 17p deletions). Despite heterogeneous mutational processes contributing to relapsed mutations across MM subtypes, increased AID/APOBEC activity is particularly associated with shorter progression time to relapse, and contributes to higher mutational burden at relapse. In addition, we identify three enhanced major clonal evolution patterns of MM relapse, independent of treatment strategies and molecular karyotypes, questioning the viability of "evolutionary herding" approach in treating drug-resistant MM. Our data show that MM relapse is associated with acquisition of new mutations and clonal selection, and suggest APOBEC enzymes among potential targets for therapy-resistant MM.

Details

Language :
English
ISSN :
2044-5385
Volume :
10
Issue :
10
Database :
MEDLINE
Journal :
Blood cancer journal
Publication Type :
Academic Journal
Accession number :
33057009
Full Text :
https://doi.org/10.1038/s41408-020-00367-2