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

Varování

Publikace nespadá pod Ekonomicko-správní fakultu, ale pod Přírodovědeckou fakultu. Oficiální stránka publikace je na webu muni.cz.

Autoři	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
Rok publikování	2015
Druh	Článek v odborném periodiku
Časopis / Zdroj	Journal of clinical oncology
Fakulta / Pracoviště MU	Přírodovědecká fakulta
Citace
www	http://jco.ascopubs.org/content/33/33/3911.long
Doi	http://dx.doi.org/10.1200/JCO.2014.59.1503
Obor	Genetika a molekulární biologie
Klíčová slova	dependent probe amplification; acute lymphoblastic-leukemia; in-istu hybridization; multiple-myeloma; genetic abnormalities; disease progression; iduced apoptosis; ATM mutations; DNA-damage; system
Popis	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.
Související projekty:	Úloha genetických abnormalit ve vývoji a progresi prekancerózy monoklonální gamapatie nejasného významu