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Mutational Spectrum, Copy Number Changes, and Outcome: Results of a Sequencing Study of Patients With Newly Diagnosed Myeloma

Lookup NU author(s): Dr Aneta Mikulasova, Professor Graham Jackson

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Abstract

PurposeAt the molecular level, myeloma is characterized by copy number abnormalities and recurrent translocations into the immunoglobulin heavy chain locus. Novel methods, such as massively parallel sequencing, have begun to describe the pattern of tumor-acquired mutations, but their clinical relevance has yet to be established.MethodsWe performed whole-exome sequencing for 463 patients who presented with myeloma and were enrolled onto the National Cancer Research Institute Myeloma XI trial, for whom complete molecular cytogenetic and clinical outcome data were available.ResultsWe identified 15 significantly mutated genes: IRF4, KRAS, NRAS, MAX, HIST1H1E, RB1, EGR1, TP53, TRAF3, FAM46C, DIS3, BRAF, LTB, CYLD, and FGFR3. The mutational spectrum is dominated by mutations in the RAS (43%) and nuclear factor-kappa B (17%) pathways, but although they are prognostically neutral, they could be targeted therapeutically. Mutations in CCND1 and DNA repair pathway alterations (TP53, ATM, ATR, and ZNFHX4 mutations) are associated with a negative impact on survival. In contrast, those in IRF4 and EGR1 are associated with a favorable overall survival. We combined these novel mutation risk factors with the recurrent molecular adverse features and international staging system to generate an international staging system mutation score that can identify a high-risk population of patients who experience relapse and die prematurely.ConclusionWe have refined our understanding of genetic events in myeloma and identified clinically relevant mutations that may be used to better stratify patients at presentation. (C) 2015 by American Society of Clinical Oncology


Publication metadata

Author(s): Walker BA, Boyle EM, Wardell CP, Murison A, Begum DB, Dahir NM, Proszek PZ, Johnson DC, Kaiser MF, Melchor L, Aronson LI, Scales M, Pawlyn C, Mirabella F, Jones JR, Brioli A, Mikulasova A, Cairns DA, Gregory WM, Quartilho A, Drayson MT, Russell N, Cook G, Jackson GH, Leleu X, Davies FE, Morgan GJ

Publication type: Article

Publication status: Published

Journal: Journal of Clinical Oncology

Year: 2015

Volume: 33

Issue: 33

Pages: 3911-3920

Print publication date: 20/11/2015

Online publication date: 17/08/2015

Acceptance date: 01/01/1900

ISSN (print): 0732-183X

ISSN (electronic): 1527-7755

Publisher: American Society of Clinical Oncology

URL: http://dx.doi.org/10.1200/JCO.2014.59.1503

DOI: 10.1200/JCO.2014.59.1503


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