Identification of Novel Oncogenes and Tumor Suppressor Genes in Newly Diagnosed Multiple Myeloma

摘要: Introduction. Identifying driver genes in multiple myeloma (MM) will have a number of key benefits as they can directly affect clinical behavior and define new targets for therapy, subgroups disease identify prognostic lesions. Here we focus on identifying tumor suppressor (TSG) oncogene (ONC) drivers MM which could potentially act novel therapy. As the majority mutations are present at Methods. We established set 1277 newly diagnosed patient samples whole exome sequencing was available. Data were derived from Myeloma XI trial, Dana-Faber Cancer Institute, The Institute Multiple Research Foundation CoMMpass study (IA1 - IA9). Mutations called using Strelka Mutect. Two strategies used to pathogenesis 1. Determine significantly mutated entire cohort each subtype (MutSigCV) 2. Identify ONCs TSGs curated cancer gene lists. defined by proportion recurrent missense (ONC score >0.4) nonsense frameshift (TSG >0.2). If both thresholds achieved larger value defining type. Expressed somatic variants analyzed sample matched RNA-seq data. Results. A total 26 statistically carrying single nucleotide (SNV) indels identified, analyzing dataset overall within major etiological subgroups. These results confirm significant 11 previously identified ( KRAS, NRAS, DIS3, BRAF, TP53, MAX, TRAF3, CYLD, RB1, FAM46C, HIST1H1E ) well 9 including UBR5 (3.5%), PRKD2 SP140 (2.4%), TRAF2 (2.1%), PTPN11 (2.3%), RASA2 (1.3%), NFKBIA TGDS CDKN1B (1.1%). Within cytogenetic sub-groups found an additional 6 IRF4 HUWE1 t(11;14), ACTG1 hyperdiploid cases, FGFR3 , MAFB non-hyperdiploid cases. Using list 116 known plus genes, determined their ONC TSG approach Vogelstein. this strategy, 13 included EGR1 (4.7%), CCND1 (2.9%) MAF (1.6%), SF3B1 (1.8%, spliceosome factor), IDH1 (0.6%) IDH2 (0.4%, increased DNA methylation). Surprisingly, DIS3 (9.9%) TP53 (5.6%) also classified oncogenes due high mutations, 73% 48% respectively. if these expressed same expected, KRAS NRAS expressed, those BRAF . Recurrent (R248 (n=4), R175, G199, Y234 (all n=3)) all (R780 (n=11), M667, H691, R820 n=2)). Understanding timing when arise is crucial targeting them effectively be clonal fraction (CCF). Examining CCF 40 saw association with higher lower CCF, indicating activating either early events or selected for, inactivating later events. Although most frequent not associated events, indicated intermediate values (median 0.65). had (>0.9). Conclusion. Oncogene activation through mutation common MM. Compared more and, therefore, natural history. Fully characterizing enhance our ability manage it effectively. Disclosures Mavrommatis: Celgene Corporation: Employment. Towfic: Immuneering Equity Ownership; Employment, Ownership. Flynt: Trotter: Translational Europe: Employment; Thakurta: Morgan: Takeda: Consultancy, Honoraria; Bristol Myers: Celgene: Honoraria, Funding.