Browse by author
Lookup NU author(s): Dr Aneta Mikulasova, Professor Graham Jackson
Full text for this publication is not currently held within this repository. Alternative links are provided below where available.
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
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
Altmetrics provided by Altmetric
