Table 4 Whole-genome/-exome sequencing.
From: High-risk disease in newly diagnosed multiple myeloma: beyond the R-ISS and IMWG definitions
| Â | Number of patients | Source of patients | Genomic findings of note | High-risk factors identified |
|---|---|---|---|---|
1273 | • Myeloma XI trial, • Dana-Faber Cancer Institute/Intergroupe Francophone du Myelome • Multiple Myeloma Research Foundation CoMMpass study | • 63 driver genes identified including novel oncogenes PTPN11 (activator of MEK/ERK signaling), PRKD2 (protein kinase D), IDH1, and IDH2 (DNA methylation), and SF3B1 (spliceosome factor) • Identified novel tumor suppressor genes including UBR5 (a ubiquitin ligase) and HUWE1 (a ubiquitin ligase that can affect MUC expression via MIZ1) • Extent of LOH was positively correlated with the APOBEC signature (P = 0.039), loss of TP53 (P = 0.001), and presence of mutations in at least 1 of 15 genes involved in homologous recombination deficiency (P < 0.001) | • Of 63 driver genes: only TP53, TRAF3, and TGDS had an impact on outcome • Driver gene mutational burden leads to worse PFS/OS • Two markers of genomic instability were associated with outcomes: APOBEC mutational signature and LOH. Other studies have also shown APOBEC mutational signatures to be high risk [64] • Identified 9 separate copy number groupings with prognostic value ◦ Cluster 7: gain of 1q, t(4;14) and t(14;16) • No correlation between ISS stage and distribution of genetic features • On multivariate modeling: ◦ t(4;14) and biallelic TP53 inactivation predictive of PFS ◦ biallelic TP53 and CKS1B amplification predictive of OS ◦ "Double-Hit": median PFS 15.4 and OS 20.7 months ▪ biallelic inactivation of TP53 or ▪ ISS III with amplification of CKS1B: | |
Bolli et al. [8] | 418 | • 373 MM patients at diagnosis • Added 45 patients from a previously published WES study | • Many genes showed an excess of variants of possible oncogenic potential but unknown pathogenesis • FAT1, FAT3, FAT4, DNAH9, DNAH11, PCLO • Sporadic oncogenic mutations with potential clinical impact in CRBN and IKZF1a • Possible novel tumor suppressors XBP1 and PRMDA which control plasma cell development • Frequently alleles of driver genes were multiply mutated -up to 5 for TP53- at a subclonal level • CCF of mutations did not influence OS save a trend towards improved OS for TP53 • Double hitb frequently noted for TP53, CYLD, and TRAF3 mutations | • "Double Hit": ◦ both t(4;14) and PRDM1: median OS of 265 days ◦ t(4;14) and TP53 mutations: median OS of 228 days • Clusters of patients stratified based on the overall number of mutations and number/type of CAs that lead to distinct effects on survival ◦ Clusters predict PFS/OS: Cluster 2 showing the worse median OS—1973 days ◦ Cluster 2 was enriched for IGH translocations, the highest number of CAs, was enriched for amp(1q), del (13), del(17p), deletions of BIRC2/3 and XBP1 and carried more TP53 mutations • The only mutated gene with a clear prognostic impact on both PFS and OS was TP53, while DNAH11 mutations conferred worse OS only • Gene-level gains/losses: 5 events conferring shorter OS, including losses of TP53/17p, CYLD/16q, FAT1, and amplifications of MYC and NRAS • Multivariate analysis for PFS: mutations in SP140 and NRAS, t(4;14), amp(1q), del(17p13) and deletions of FAT1 and PRDM1 • Multivariate analysis for OS: t(4;14), amp(1q), del(17p13), del(1p) |
1151 in total | Data from patients receiving treatment in the context of clinical trials as well as with real word regimens were included | • 55 genes were significantly mutated and there was a 65% overlap with the MGP • The linker histones HIST1H1B, HIST1H1D, HIST1H1E, and HIST1H2BK all showed a distinctive pattern of missense mutations clustered in the highly conserved globular domain • FUBP1, an important regulator of MYC transcription, showed an excess of splice site and nonsense mutations, emerging as a potential tumor suppressor gene in MM | • Multivariate analysis for early PDc ◦ TP53 mutation (OR, 3.78, P < 0.001) ◦ High lactate dehydrogenase levels (OR, 3.15, P=0.006), ◦ IgL-chain translocation (OR, 2.25, P = 0.033) ◦ IGLL5 mutation (OR, 2.15, P = 0.007) • A trend was found for gain(1q) and amp(1q) in regards to early PD; but this did correlate with early death within 24 months • Survival analysis revealed significantly shorter PFS in patients with greater than average somatic missense mutation load (49.3 vs. 72.6% 2-year PFS, P = 0.0023) and predicted expressed neoantigen load (N = 214, 55.5 vs. 72.9% 2-year PFS, P = 0.0028) |
