Abstract
We examined a set of 805 cases that underwent DNA sequencing using the FoundationOne Heme (F1H) targeted sequencing panel and gene expression profiling. Known and likely variant calls from the mutational data were analyzed for significant associations with gene expression defined translocation cyclin D (TC) molecular subgroups. The spectrum of KRAS, NRAS, and BRAF codon mutations varied across subgroups with NRAS mutations at Q61 codon being common in hyperdiploid (HRD) and t(11;14) myeloma while being rare in MMSET and MAF. In addition, the presence of RAS-RAF mutations was inversely associated with NFκB pathway activation in all subgroups excluding MAF. In the MMSET subgroup, cases with low FGFR3 expression frequently had RAS-RAF mutations. Conditional inference tree analysis determined that mutation and homozygous deletion of TP53, CDKN2C, and RB1 were key prognostic factors associated with adverse outcome in a non-relapse clinical setting. In conclusion, this study highlights the heterogeneity in the distribution and clinical outcomes of RAS codon and other mutations in multiple myeloma dependent upon primary molecular subgroup.
Highlights
Analysis of myeloma plasma cells using cytogenetics and fluorescence in-situ hybridization (FISH) has formed the basis of genetic subgrouping in myeloma (MM) [1,2,3]
We show for the first time a clear difference in mutational spectrum across the molecular subgroups of MM defined by an updated translocation cyclin D (TC) algorithm
We www.impactjournals.com/oncotarget show that not observed in cases with KRAS mutations (NRAS) mutations at Q61 are common in HRD and t(11;14) myeloma but rare in MMSET and MAF
Summary
Analysis of myeloma plasma cells using cytogenetics and fluorescence in-situ hybridization (FISH) has formed the basis of genetic subgrouping in myeloma (MM) [1,2,3] These investigations generated etiological groups based upon either the presence of a translocation into the immunoglobulin heavy chain (IGH) locus (40%) or hyperdiploidy (HRD). Further analysis identified the overexpression of a D-group cyclin as a key aberration that is uniformly dysregulated as part of a convergent evolutionary pathway integrating all of the genetic events leading to MM [4, 5] In this respect, translocations into the 11q13 locus directly deregulate CCND1; 6p21 CCND3; and 4p16 (MMSET), 16q23 (MAF), and 20q12 (MAFB) indirectly deregulate CCND2. This classification framework was expanded upon by the HOVON group with additional subgroups defined by secondary features, e.g. NFκB activation and PRL3 expression [8]
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