1Genetic events in the pathogenesis of multiple myeloma
Section snippets
MM is a plasmablast/plasma-cell tumor of post-germinal-center B cells
Post-GC B cells that have undergone productive somatic hypermutation, antigen selection, and IgH switching can generate plasmablasts (PBs), which typically migrate to the bone marrow (BM) microenvironment that enables differentiation into long-lived plasma cells (PCs).5 Importantly, non-IgM MGUS and MM are monoclonal tumors that are phenotypically similar to PBs/long-lived PCs, including a strong dependence on the BM microenvironment for survival and growth.6 In contrast to normal long-lived
Stages of MM
It is thought that a PC tumor must include about 109 cells to produce enough monoclonal Ig (M-Ig) or monoclonal IgL (M-IgL) to be detected by serum and/or urine electrophoresis.8 However, the recent development of a serum free IgL assay has significantly reduced the number of PC tumor cells that can be detected.9 This includes an increased ability to detect low levels of M-Ig (or M-IgL in the approximately 15% of MGUS and MM tumors that express only IgL).10 For MGUS, serum M-Ig usually is 0.5–3
Ig translocations are present in a majority of MM tumors
Like other post-GC B-cell tumors, translocations involving the IgH locus (14q32) or one of the IgL loci (κ, 2p12 or λ, 22q11) are common.15 Mostly they are mediated by errors in one of the three B-cell-specific DNA modification mechanisms: VDJ recombination, IgH switch recombination, or somatic hypermutation. With rare exceptions, these translocations result in dysregulated or increased expression of an oncogene that is positioned near one or more of the strong Ig enhancers on the derivative 14
Seven recurrent IgH translocations appear to represent primary oncogenic events
Recently, IgH translocations involving cyclin D2 and MAFA have been reported.22 Thus, there are now seven recurrent chromosomal partners and oncogenes that are involved in IgH translocations in approximately 40% of MM tumors. There are three recurrent IgH translocation groups6, 23, 24, *25, 26, 27, 28:
- 1.
CYCLIN D: 11q13 (Cyclin D1), 15%; 12p13 (Cyclin D2), <1%; 6p21 (Cyclin D3), 2%;
- 2.
MAF: 16q23 (c-MAF), 5%; 21q12 (MAFB), 2%; 8q24.3 (MAFA), <1%; and
- 3.
MMSET/FGFR3: 4p16 (MMSET and usually FGFR3), 15%.
The
Cyclin D translocation group
The t(11;14) translocation in MM is unusual in that the translocation breakpoints involve VDJ and switch regions with a similar frequency. By contrast, t(4;14) and t(14;16) breakpoints are always and mostly, respectively, located within or near IgH switch regions.16, 31 The prevalence of t(11;14) translocations is approximately 15% in both MGUS18, 32 and MM21, 33, but the prevalence is >40% in primary amyloidosis (AL)34, despite the fact that AL is thought to be MGUS with a minimal tumor mass
MAF translocation group
Tumors with translocations affecting any of the three MAF genes share a very distinctive gene expression profile.35 Many of the genes that are up-regulated in these tumors are thought to be shared targets for all three MAF transcription factors. Notably, these putative targets include CCND2 and other genes (ITGB7, ARK5) that appear to affect the phenotype of the tumor cells, and its potential interactions with the bone-marrow microenvironment*30, 36, although the transcription targets critical
MMSET/FGFR3 translocation group
The prevalence of this translocation appears to be substantially lower in MGUS/SMM than in MM14, 21, 32, *35, 37, although one study reported only a slightly decreased prevalence in MGUS/SMM compared to MM.18 Although MMSET is dysregulated in all cases, nearly one third of patients with the t(4;14) translocation do not express FGFR3. The lack of FGFR3 expression seems to be related mainly to the loss of der(14), but in some cases der(14) is present and other mechanisms account for the loss of
Two recurrent translocations from different translocation groups in the same tumor cell
Rare MGUS or MM tumors, or HMCLs, can have two different recurrent translocations (Kuehl, unpublished).6, 18 In all of these cases the translocations are from two different translocation groups, with all combinations having been observed. In some of these cases, one of the translocations clearly is secondary, since it is found in only a subset of tumor cells, or is presumptively secondary since it is a complex translocation or insertion. These rare examples suggest that the three different
MYC translocations: a paradigm for secondary translocations
Translocations that involve a MYC gene are rare or absent in MGUS, but occur in 15% of MM tumors, 44% of advanced tumors, and nearly 90% of HMCLs. Mostly, these rearrangements involve c-MYC, but about 2% of primary tumors ectopically express N-MYC (and presumably have N-MYC translocations, as confirmed in some cases), and an L-MYC rearrangement has been identified in only one HMCL. These translocations, often heterogeneous in primary tumors, are usually complex rearrangements or insertions,
Secondary Ig translocations
Approximately 10–20% of IgH translocations in MGUS and MM do not involve MYC or one of the seven recurrent partners described above, but partner loci have rarely been identified.18, 19, 21, 44, 45, 46 In contrast to IgH translocations involving recurrent partners, these IgH translocations, as well as most translocations involving IgL loci, share many similarities with MYC translocations: breakpoints not in or near IgH switch or V(D)J regions, unbalanced or complex structures, and occurring with
Chromosome content seems to be associated with at least two different pathogenic pathways
There is a clear consensus that chromosome content reflects at least two pathways of pathogenesis. Approximately half of tumors are HRD (48–75 chromosomes), and typically have multiple trisomies involving chromosomes 3,5, 7, 9, 11, 15, 19, and 21, but only infrequently (<10%) have one of the recurrent IgH translocations. NHRD tumors (<48 and/or >75 chromosomes) usually (∼70%) have one of the recurrent IgH translocations.47, 48, 49, 50 Tumors that have a t(11;14) translocation may represent a
Loss of chromosome 13/13q14 (Δ13)
About 50% of MM tumors19, 32, 51, 52, 53 and 40–50% of MGUS18, 32, 54 tumors have Δ13 in most tumor cells, suggesting that this is often an early event in pathogenesis. In most cases, Δ13 represents whole-chromosome monosomy55, 56, but in a subset of tumors the common deleted region seems to be located at 13q1446, 55, 56, 57, 58, 59, although no critical molecular abnormality has been confirmed at this time. The retinoblastoma gene falls within the minimally deleted region; however,
Gain of chromosome 1q21
Using a combination of FISH, array comparative genomic hybridization (aCGH), and GEP, a number of laboratories has determined that there is a gain of sequences – and corresponding increased gene expression – at 1q21 in 30–40% of tumors. These gains are concentrated substantially in those tumors that have a t(4;14) or t(14;16), or have a high proliferation expression index.62, 63, 64 Although not formally proven by examination of paired samples, the gain of chromosome 1q21 sequences may occur de
Activating RAS mutations
The prevalence of activating N- or K-RAS mutations is about 30–40% of newly diagnosed MM tumors, with only a small increase occurring during tumor progression.66, 67 The prevalence is about 45% in HMCLs.29 Importantly, less than 5% of MGUS tumors have RAS mutations, consistent with the hypothesis that RAS mutations may mark, if not mediate, the MGUS-to-MM transition.66, 68 Recent studies indicate that the prevalence of RAS mutations is substantially higher in tumors that express Cyclin D1
Abnormalities of p53 gene and chromosome 17p loss
Mutations of p53 are relatively rare in newly diagnosed MM, occurring in approximately 5% of tumors. However, the frequency of mutations appears to increase with disease stage, and is about 30% in PCL and 65% in HMCLs.70, 71, 72, 73 Deletion (mainly mono-allelic) of p53, as detected by interphase FISH, occurs in about 10% of MM tumors and approximately 40% of PCL and HMCLs.52, 74 However, it should be noted that there is no definitive evidence that the critical chromosome 17p loss is TP53.
Activation of NFKB pathway
It has been suggested in the past that activation of the NFKB pathway is important in the pathogenesis of MM, but little is known about the prevalence of NFKB activation or mechanisms that cause NFKB activation. Recently a promiscuous array of mutations that result in constitutive activation of the NFKB pathway have been identified in about 20% of patient samples and 20/44 HMCLs. The most common event is inactivating mutation of TRAF3 in 13% of patients. In addition, inactivating mutations of
Dysregulation of a CYCLIN D gene: a unifying and early oncogenic event in MGUS and MM
It has been proposed that dysregulation of a CYCLIN D gene provides a unifying, early oncogenic event in MGUS and MM.35 About 25% of MM tumors have an IgH translocation that directly dysregulates a CYCLIN D gene or a MAF gene encoding a transcription factor that markedly up-regulates CYCLIN D2. Although MM tumors with a t(4;14) express moderately high levels of CYCLIN D2, the cause of increased CYCLIN D2 expression remains unknown. Despite the fact that normal BM PCs express little or no
Disruption of other component of the RB pathway: p16INK4A, p18INK4B, RB1
Besides CYCLIN D, other components of the RB pathway are also commonly dysregulated in MM. The p16INK4A and p15INK4A genes are methylated in about 20–30% of MGUS and MM tumors, and in most HMCLs.44 Two recent studies showed that most MM tumors express little or no p16, regardless of whether or not the gene is methylated.78, 79 This suggests that low expression mostly is not due to methylation, which may be an epi-phenomenon. Despite one example of an individual with a germline mutation and loss
An updated model for the molecular pathogenesis of non-IgM MGUS and MM
The current model has been updated from an earlier version48 mainly by the inclusion of molecular events that dysregulate the NFKB pathway (Figure 1). As summarized above, there are two pathways of pathogenesis: an NHRD pathway and an HRD pathway. Altogether, there are four early and partially overlapping events for which the precise timing is unknown: IgH translocations mediated mainly by errors in switch recombination or somatic hypermutation in germinal center B cells, hyperdiploidy
Genetic classification systems
Recent technological advances have resulted in the ability to assess genomic aberrations at both the DNA and RNA levels in a global fashion. This has resulted in a number of new classifications with biological and clinical relevance.
Prognostic implications of genetics in MM
Besides providing insights into the biology of disease pathogenesis and evolution, genetic abnormalities are also powerful prognostic factors in MM.44, 85 A recent large international study developed a reproducible staging system (ISS staging system) applicable across geographical regions, comprising two routine clinical tests: serum albumin and β2-microglobulin.86 However, genetic factors were not fully assessed in this study. A large study from the IFM group (Intergroupe Francophone du
Summary
The study of genetics has greatly enhanced our understanding of the pathogenesis and underlying biological and clinical heterogeneity of MM. In particular, high-risk genetic subtypes have been identified and shown to have differential benefit for certain therapies. A prime example is that treatment with bortezomib seems to overcome the adverse prognosis following HDT associated with t(4;14). In these patients, one may choose not to administer conventional therapy but to start with novel agents.
Acknowledgements
The review presented here was substantially influenced by the presentation of data and discussion at the 2nd Multiple Myeloma Genetics/Pathogenesis Roundtable in June 2006, Madonna di Campiglio. We would like to acknowledge the support of the McCarty Foundation and the Multiple Myeloma Research Foundation for their support for this meeting. In addition we would like to acknowledge the researchers who presented their work and ideas: Ken Anderson, Herve Avet-Loiseau, Bart Barlogie, Leif
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