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Copy number evolution and its relationship with patient outcome—an analysis of 178 matched presentation-relapse tumor pairs from the Myeloma XI trial

Lookup NU author(s): Professor Graham Jackson

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2020, The Author(s).Structural chromosomal changes including copy number aberrations (CNAs) are a major feature of multiple myeloma (MM), however their evolution in context of modern biological therapy is not well characterized. To investigate acquisition of CNAs and their prognostic relevance in context of first-line therapy, we profiled tumor diagnosis–relapse pairs from 178 NCRI Myeloma XI (ISRCTN49407852) trial patients using digital multiplex ligation-dependent probe amplification. CNA profiles acquired at relapse differed substantially between MM subtypes: hyperdiploid (HRD) tumors evolved predominantly in branching pattern vs. linear pattern in t(4;14) vs. stable pattern in t(11;14). CNA acquisition also differed between subtypes based on CCND expression, with a marked enrichment of acquired del(17p) in CCND2 over CCND1 tumors. Acquired CNAs were not influenced by high-dose melphalan or lenalidomide maintenance randomization. A branching evolution pattern was significantly associated with inferior overall survival (OS; hazard ratio (HR) 2.61, P = 0.0048). As an individual lesion, acquisition of gain(1q) at relapse was associated with shorter OS, independent of other risk markers or time of relapse (HR = 2.00; P = 0.021). There is an increasing need for rational therapy sequencing in MM. Our data supports the value of repeat molecular profiling to characterize disease evolution and inform management of MM relapse.


Publication metadata

Author(s): Croft J, Ellis S, Sherborne AL, Sharp K, Price A, Jenner MW, Drayson MT, Owen RG, Chown S, Lindsay J, Karunanithi K, Hunter H, Gregory WM, Davies FE, Morgan GJ, Cook G, Atanesyan L, Savola S, Cairns DA, Jackson G, Houlston RS, Kaiser MF

Publication type: Article

Publication status: Published

Journal: Leukemia

Year: 2020

Pages: epub ahead of print

Online publication date: 01/12/2020

Acceptance date: 14/11/2020

Date deposited: 04/02/2021

ISSN (print): 0887-6924

ISSN (electronic): 1476-5551

Publisher: Springer Nature

URL: https://doi.org/10.1038/s41375-020-01096-y

DOI: 10.1038/s41375-020-01096-y


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