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-κB (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.

Brian A Walker Eileen M Boyle Christopher P Wardell Alex Murison Dil B Begum Nasrin M Dahir Paula Z Proszek David C Johnson Martin F Kaiser Lorenzo Melchor Lauren 1 Aronson Charlotte Pawlyn Fabio Mirabella John R Jones Annamaria Brioli Faith E Davies and Gareth J Morgan The Institute of Cancer Research London; Matthew Scales The Institute of Cancer Research Surrey; David A Cairns Walter M Gregory and Ana Quartilho University of Leeds; Gordon Cook St James's University Hospital Leeds; Mark T Drayson University of Birmingham Birmingham; Nigel Russell Nottingham University Hospital Nottingham; Graham H Jackson Newcastle University Newcastle upon Tyne United Kingdom; Aneta Mikulasova Masaryk University Brno Czech Republic; and Xavier Leleu Hôpital C Huriez Centre Hospitalier Régional Universitaire de Lille Lille France

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Morgan GJ, Walker BA, Davies FE. The genetic architecture of multiple myeloma. Nat Rev Cancer. 2012;12:335–48. PubMed

Boyd KD, Ross FM, Chiecchio L, et al. A novel prognostic model in myeloma based on co-segregating adverse FISH lesions and the ISS: analysis of patients treated in the MRC Myeloma IX trial. Leukemia. 2012;26:349–55. PubMed PMC

Avet-Loiseau H, Durie BG, Cavo M, et al. Combining fluorescent in situ hybridization data with ISS staging improves risk assessment in myeloma: an International Myeloma Working Group collaborative project. Leukemia. 2013;27:711–7. PubMed PMC

Klein U, Jauch A, Hielscher T, et al. Chromosomal aberrations +1q21 and del(17p13) predict survival in patients with recurrent multiple myeloma treated with lenalidomide and dexamethasone. Cancer. 2011;117:2136–44. PubMed

Greipp PR, San Miguel J, Durie BG, et al. International staging system for multiple myeloma. J Clin Oncol. 2005;23:3412–20. PubMed

Walker BA, Wardell CP, Johnson DC, et al. Characterization of IGH locus breakpoints in multiple myeloma indicates a subset of translocations appear to occur in pregerminal center B cells. Blood. 2013;121:3413–9. PubMed

Ross FM, Avet-Loiseau H, Ameye G, et al. Report from the European Myeloma Network on interphase FISH in multiple myeloma and related disorders. Haematologica. 2012;97:1272–7. PubMed PMC

Avet-Loiseau H, Attal M, Moreau P, et al. Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myelome. Blood. 2007;109:3489–95. PubMed

Avet-Loiseau H, Li C, Magrangeas F, et al. Prognostic significance of copy-number alterations in multiple myeloma. J Clin Oncol. 2009;27:4585–90. PubMed PMC

Fonseca R, Blood E, Rue M, et al. Clinical and biologic implications of recurrent genomic aberrations in myeloma. Blood. 2003;101:4569–4575. PubMed

Walker BA, Wardell CP, Brioli A, et al. Translocations at 8q24 juxtapose MYC with genes that harbor superenhancers resulting in overexpression and poor prognosis in myeloma patients. Blood Cancer J. 2014;4:e191. PubMed PMC

Jenner MW, Leone PE, Walker BA, et al. Gene mapping and expression analysis of 16q loss of heterozygosity identifies WWOX and CYLD as being important in determining clinical outcome in multiple myeloma. Blood. 2007;110:3291–300. PubMed

Lohr JG, Stojanov P, Carter SL, et al. Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy. Cancer Cell. 2014;25:91–101. PubMed PMC

Chapman MA, Lawrence MS, Keats JJ, et al. Initial genome sequencing and analysis of multiple myeloma. Nature. 2011;471:467–72. PubMed PMC

Bolli N, Avet-Loiseau H, Wedge DC, et al. Heterogeneity of genomic evolution and mutational profiles in multiple myeloma. Nat Commun. 2014;5:2997. PubMed PMC

Kozarewa I, Rosa-Rosa JM, Wardell CP, et al. A modified method for whole exome resequencing from minimal amounts of starting DNA. PLoS ONE. 2012;7:e32617. PubMed PMC

Boeva V, Popova T, Bleakley K, et al. Control-FREEC: a tool for assessing copy number and allelic content using next-generation sequencing data. Bioinformatics. 2012;28:423–5. PubMed PMC

Rausch T, Zichner T, Schlattl A, et al. DELLY: structural variant discovery by integrated paired-end and split-read analysis. Bioinformatics. 2012;28:i333–i339. PubMed PMC

Kaiser MF, Walker BA, Hockley SL, et al. A TC classification-based predictor for multiple myeloma using multiplexed real-time quantitative PCR. Leukemia. 2013;27:1754–7. PubMed

Alpar D, de Jong D, Holczer-Nagy Z, et al. Multiplex ligation-dependent probe amplification and fluorescence in situ hybridization are complementary techniques to detect cytogenetic abnormalities in multiple myeloma. Genes Chromosomes Cancer. 2013;52:785–93. PubMed

Schwab CJ, Jones LR, Morrison H, et al. Evaluation of multiplex ligation-dependent probe amplification as a method for the detection of copy number abnormalities in B-cell precursor acute lymphoblastic leukemia. Genes Chromosomes Cancer. 2010;49:1104–13. PubMed

Boyle EM, Proszek P, Kaiser M, et al. A molecular diagnostic approach able to detect the recurrent genetic prognostic factors typical of presenting myeloma. submitted. PubMed PMC

JAGS 3.4.0. Just Another Gibbs Sampler: (ed JAGS 3.4.0.) 2013.

Nuijten M, Wetzels R, Matzke D, Dolan CV, Wagenmakers EJ. Default Bayesian hypothesis tests for correlation, partial correlation, and mediation, (ed 1.0) 2014. PubMed

Wetzels R, Wagenmakers EJ. A default Bayesian hypothesis test for correlations and partial correlations. Psychon Bull Rev. 2012;19:1057–64. PubMed PMC

Kass R, Raferty A. Bayes Factors. Journal of the American Statistical Association. 1995;90:773–795.

Wei T. Corrplot: Visualization of a correlation matrix. 2013.

R development Core Team . R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing. R Foundation for statistical Computing; Vienna, Austria: 2013.

Therneau T, Grambsch P. Modeling Survival Data: Extending the Cox Model. Springer; New York: 2000.

Therneau T. A Package for Survival Analysis in S, (ed R package version 2.37-7) 2014.

Hothorn T, Hornik K, van de Wiel M, et al. Implementing a Class of Permutation Tests: The {coin} Package. Journal of Statistical Software. 2008;28:1–23. PubMed

Hothorn T, Hornik K, van de Wiel M, et al. A Lego System for Conditional Inference. The American Statistician. 2006;60:257–263.

Qiu Weiliang, C J, Lazarus Ross, Rosner Bernard, Jing Ma. powerSurvEpi: Power and sample size calculation for survival analysis of epidemiological studies, (ed 0.0.6) 2012.

Harrell FE. REGRESSION MODELING STRATEGIES with Applications to Linear Models, Logistic Regression, and Survival Analysis. Springer; 2001.

Annunziata CM, Davis RE, Demchenko Y, et al. Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma. Cancer Cell. 2007;12:115–30. PubMed PMC

Chen L, Wang S, Zhou Y, et al. Identification of early growth response protein 1 (EGR-1) as a novel target for JUN-induced apoptosis in multiple myeloma. Blood. 2010;115:61–70. PubMed PMC

Lode L, Eveillard M, Trichet V, et al. Mutations in TP53 are exclusively associated with del(17p) in multiple myeloma. Haematologica. 2010;95:1973–6. PubMed PMC

Skowronska A, Austen B, Powell JE, et al. ATM germline heterozygosity does not play a role in chronic lymphocytic leukemia initiation but influences rapid disease progression through loss of the remaining ATM allele. Haematologica. 2012;97:142–6. PubMed PMC

Guarini A, Marinelli M, Tavolaro S, et al. ATM gene alterations in chronic lymphocytic leukemia patients induce a distinct gene expression profile and predict disease progression. Haematologica. 2012;97:47–55. PubMed PMC

Fang NY, Greiner TC, Weisenburger DD, et al. Oligonucleotide microarrays demonstrate the highest frequency of ATM mutations in the mantle cell subtype of lymphoma. Proc Natl Acad Sci U S A. 2003;100:5372–7. PubMed PMC

Meier M, den Boer ML, Hall AG, et al. Relation between genetic variants of the ataxia telangiectasia-mutated (ATM) gene, drug resistance, clinical outcome and predisposition to childhood T-lineage acute lymphoblastic leukaemia. Leukemia. 2005;19:1887–95. PubMed

Austen B, Barone G, Reiman A, et al. Pathogenic ATM mutations occur rarely in a subset of multiple myeloma patients. Br J Haematol. 2008;142:925–33. PubMed

Zighelboim I, Schmidt AP, Gao F, et al. ATR mutation in endometrioid endometrial cancer is associated with poor clinical outcomes. J Clin Oncol. 2009;27:3091–6. PubMed PMC

Matsuoka S, Ballif BA, Smogorzewska A, et al. ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science. 2007;316:1160–6. PubMed

Mu JJ, Wang Y, Luo H, et al. A proteomic analysis of ataxia telangiectasia-mutated (ATM)/ATM-Rad3-related (ATR) substrates identifies the ubiquitin-proteasome system as a regulator for DNA damage checkpoints. J Biol Chem. 2007;282:17330–4. PubMed

Chudnovsky Y, Kim D, Zheng S, et al. ZFHX4 interacts with the NuRD core member CHD4 and regulates the glioblastoma tumor-initiating cell state. Cell Rep. 2014;6:313–24. PubMed PMC

Zhu YX, Braggio E, Shi CX, et al. Identification of cereblon-binding proteins and relationship with response and survival after IMiDs in multiple myeloma. Blood. 2014;124:536–45. PubMed PMC

Boone DN, Qi Y, Li Z, et al. Egr1 mediates p53-independent c-Myc-induced apoptosis via a noncanonical ARF-dependent transcriptional mechanism. Proc Natl Acad Sci U S A. 2011;108:632–7. PubMed PMC

Wirth M, Stojanovic N, Christian J, et al. MYC and EGR1 synergize to trigger tumor cell death by controlling NOXA and BIM transcription upon treatment with the proteasome inhibitor bortezomib. Nucleic Acids Res. 2014 PubMed PMC

Joslin JM, Fernald AA, Tennant TR, et al. Haploinsufficiency of EGR1, a candidate gene in the del(5q), leads to the development of myeloid disorders. Blood. 2007;110:719–26. PubMed PMC

Mulligan G, Lichter DI, Di Bacco A, et al. Mutation of NRAS but not KRAS significantly reduces myeloma sensitivity to single-agent bortezomib therapy. Blood. 2014;123:632–9. PubMed PMC

Takahashi N, Yamada Y, Taniguchi H, et al. Clinicopathological features and prognostic roles of KRAS, BRAF, PIK3CA and NRAS mutations in advanced gastric cancer. BMC Res Notes. 2014;7:271. PubMed PMC

Bruce S, Leinonen R, Lindgren CM, et al. Global analysis of uniparental disomy using high density genotyping arrays. J.Med.Genet. 2005;42:847–851. PubMed PMC

Mutation landscape of multiple myeloma measurable residual disease: identification of targets for precision medicine

Epidemiology, genetics and treatment of multiple myeloma and precursor diseases

Heterogenous mutation spectrum and deregulated cellular pathways in aberrant plasma cells underline molecular pathology of light-chain amyloidosis

Natural history of multiple myeloma with de novo del(17p)

The spectrum of somatic mutations in monoclonal gammopathy of undetermined significance indicates a less complex genomic landscape than that in multiple myeloma

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