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

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Authors	WALKER Brian BOYLE Eileen WARDELL Christopher MURISON Alex BEGUN Dil DAHIR Nasrin PROSZEK Paula JOHNSON David KAISER Martin MELCHOR Lorenzo ARONSON Lauren SCALES Matthew PAWLYN Charlotte MIRABELLA Fabio JONES John BRIOLI Annamaria MIKULÁŠOVÁ Aneta CAIRNS David WALTER Gregory QUARTILHO Ana DRAYSON Mark RUSSEL Nigel COOK Gordon JACKSON Graham LELEU Xavier DAVIES Faith MORGAN Gareth
Year of publication	2015
Type	Article in Periodical
Magazine / Source	Journal of clinical oncology
MU Faculty or unit	Faculty of Science
Citation
Web	http://jco.ascopubs.org/content/33/33/3911.long
Doi	http://dx.doi.org/10.1200/JCO.2014.59.1503
Field	Genetics and molecular biology
Keywords	dependent probe amplification; acute lymphoblastic-leukemia; in-istu hybridization; multiple-myeloma; genetic abnormalities; disease progression; iduced apoptosis; ATM mutations; DNA-damage; system
Description	PURPOSE: At 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. METHODS:We 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. RESULTS: We 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-kappaB (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. CONCLUSION: We have refined our understanding of genetic events in myeloma and identified clinically relevant mutations that may be used to better stratify patients at presentation.
Related projects:	Úloha genetických abnormalit ve vývoji a progresi prekancerózy monoklonální gamapatie nejasného významu