Genomic Aberrations in Multiple Myeloma

  • Salomon Manier
  • Karma Salem
  • Siobhan V. Glavey
  • Aldo M. Roccaro
  • Irene M. Ghobrial
Part of the Cancer Treatment and Research book series (CTAR, volume 169)


Multiple myeloma (MM) is a genetically complex disease. The past few years have seen an evolution in cancer research with the emergence of next-generation sequencing (NGS), enabling high throughput sequencing of tumors—including whole exome, whole genome, RNA, and single-cell sequencing as well as genome-wide association study (GWAS). A few inherited variants have been described, counting for some cases of familial disease. Hierarchically, primary events in MM can be divided into hyperdiploid (HDR) and nonhyperdiploid subtypes. HRD tumors are characterized by trisomy of chromosomes 3, 5, 7, 9, 11, 15, 19, and/or 21. Non-HRD tumors harbor IGH translocations, mainly t(4;14), t(6;14), t(11;14), t(14;16), and t(14;20). Secondary events participate to the tumor progression and consist in secondary translocation involving MYC, copy number variations (CNV) and somatic mutations (such as mutations in KRAS, NRAS, BRAF, P53). Moreover, the dissection of clonal heterogeneity helps to understand the evolution of the disease. The following review provides a comprehensive review of the genomic landscape in MM.


Genomics Next-generation sequencing Myeloma Clonal evolution 

1 Introduction

Multiple myeloma (MM) is a genetically complex and heterogeneous disease resulting from a multiple genomic events leading to tumor development and progression. Uncovering and dissecting true driver events in MM might provide rational for new potential targets and therapeutic option in the disease. All MM are preceded by a monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM). This model of the disease provides a framework to understand the genomic hierarchy in MM. Events found at MGUS stages are likely to be primary events and involved in tumor development, in contrary, events present at the MM stage and absent in MGUS are likely to be secondary events leading to tumor progression. Similarly, the study of clonal heterogeneity—defining clonal or subclonal genomic events helps also to dissect the phylogeny of tumors. Hierarchically, primary events are usually divided into hyperdiploid (HDR) and nonhyperdiploid subtypes. HRD tumors are characterized by trisomy of chromosomes 3, 5, 7, 9, 11, 15, 19, and/or 21. Non-HRD tumors harbor IGH translocations, mainly t(4;14), t(6;14), t(11;14), t(14;16), and t(14;20). Secondary events are required for tumor progression. Most of the copy number variations (CNV), MYC translocations and somatic mutations in MAPK, NFkB, and DNA repair pathways are only seen at MM stages and not in premalignant stages—so potential secondary events. However, the distinction between driver and passenger events is a current challenge to interpret correctly the genomic landscape of MM.

2 Inherited Variants

Although lifestyle or environmental exposures have not been consistently linked to the incidence of MM, there seems to be a two to fourfold elevated risk of MM in relatives of individuals with the disease [1]. This has been postulated to be a consequence of the co-inheritance of multiple low-risk variants. Investigating these families further and performing genome-wide association studies (GWAS) on large patient populations, three genetic loci were associated with a modest but increased risk of developing MM. These include 3p22.1 (rs1052501, in ULK4), 7p15.3 (rs4487645, surrounding by DNAH11 and CDCA7L) and 2p23.3 (rs6746082, surrounding by DNMT3A and DTNB) [2]. A follow-up study by the same group, including 4,692 individuals with MM and 10,990 controls, revealed four new loci: 3q26.2 (rs10936599, surrounding by MYNN and TERC), 6p21.33 (rs2285803 in PSORS1C2), 17p11.2 (rs4273077 in TNFRSF13B) and 22q13.1 (rs877529 in CBX7) [3]. These seven identified loci provide further evidence for an inherited genetic susceptibility to MM and reportedly account for ~13 % of the familial risk of MM. The complete functional role of each of these candidate genes remains to be elucidated. The authors found no association between genotypes and the expression level of their genes. Interestingly, in another GWAS study, the same team identified a strong association between the variant rs603965, responsible for c807G > A polymorphism in CCND1 and the translocation t(11;14)(q13;q32), in which CCND1 is placed under the control of the immunoglobulin heavy (IGH) chain enhancer [4]. In this model, a constitutive genetic factor is associated with risk of a specific chromosomal translocation. Based on these initial studies, it is likely that more susceptibility loci will be identified in the future and possibly correlated to specific MM subtypes. For example, it has been largely reported that African-Americans have a higher risk of developing MM than Caucasians; however, no potential genetic variants have been identified to date [5]. Moreover, uncovering the functional role of these 7 SNPs significantly associated with MM might help to advance our understanding of MM oncogenesis.

3 Chromosomal Translocations

In MM, the large majority of chromosomal translocations involve chromosome 14, and specifically the IGH locus on 14q32.33, placing a partner gene under the control of the IGH enhancer. These translocations are generated by abnormal class switch recombination (CSR) events and are usually present in all clonal cells. They are also detectable in monoclonal gammopathy of unknown significance (MGUS), consistent with their early development in MM oncogenesis. Five major chromosomal partners—t(4;14), t(6;14), t(11;14), t(14;16), and t(14;20)—seem to impart a selective advantage to the clone by up regulating expression of specific oncogenes—MMSET and FGFR3, CCND3, CCND1, MAF, and MAFB, respectively [6]. It is likely that all these translocations lead to deregulation in the cell cycle G1/S transition, which has been described as a key early molecular abnormality in MM. This can be direct through t(11;14) and t(6;14) deregulating CCND1 and CCND3, respectively [7, 8]. In t(14;16), this is modulated through MAF which up regulates CCND2 by directly binding to its promoter [9] while in t(4;14), the exact mechanism is still uncertain but the translocation of FGFR3 and MMSET to the IGH enhancer is known to also up regulate CCND2 [6]. Recently, mutations involving the MYC locus have been identified in MM.

Translocation (4;14) is observed in about 15 % of MM cases [10] and has been associated with an adverse prognosis in a variety of clinical settings [11, 12, 13, 14]. The juxtaposition results in deregulation in the expression of FGFR3 and MMSET/WHSC1 [15]. The breakpoints all reside between FGFR3 and MMSET resulting in overexpression of FGFR3 in 70 % of the cases and MMSET in all cases [16, 17, 18]. MMSET is a methyl-transferase protein, whose up regulation leads to the methylation of histone H3K36, thus regulates expression of several genes [19]. MMSET has been shown also to regulate histone H4K20 methylation and recruit 53BP1 at DNA damage sites [20]. FGFR3 is a tyrosine kinase receptor oncogene activated by mutations in several solid tumor types. Notably, FGFR3 is up regulated in only 70 % of patients with the translocation because of an unbalanced translocation with loss of the telomeric part of chromosome 4, bearing FGFR3 [12, 17, 21]. This suggests that MMSET is the main molecular target of the translocation. Interestingly, despite the poor prognosis associated with t(4;14), a survival advantage in these patients has been demonstrated through early treatment with the proteasome inhibitor Bortezomib [22, 23].

Translocation (6;14) is a rare translocation present in only about 2 % of MM patients [10] and results in the direct up regulation of CCND3 via juxtaposition to the IGH enhancers [8, 11]. The breakpoints are all located 5’ of the gene [16]. The overall prognostic impact of this translocation is neutral [24].

Translocation (11;14) is the most frequent translocation cited as being present in about 15–20 % of patients with MM [7]. Normally B cells express cyclin D2 and D3 but not D1. However, due to the translocation juxtaposing CCND1 to the IGH enhancer, its expression is deregulated. The breakpoints seem to be located 5’ of CCND1 [16]. In terms of prognosis, this translocation is considered as neutral, however, Walker et al. recently showed that in 10 % of t(11;14) a CCND1 mutation co-occurs and the combination is associated with a poor prognosis when compared with non-mutated t(11;14) patients [25].

Translocation (14;16) is estimated to be present in about 5–10 % of patients with MM and results in the overexpression of the MAF oncogene splice variant c-MAF, a transcription factor which up regulates a number of genes, including CCND2 by binding directly to its promoter [9, 26]. Breakpoints are located 3’ of MAF within the last exon of WWOX, a known tumor suppressor [16]. Though t(14;16) was associated with a poor prognosis in a number of clinical series [13, 27], a more recent retrospective multivariable analysis on 1003 newly diagnosed MM patients showed t(14;16) is not associated with a poor prognosis [27].

Translocation (14;20) is present in about 1 % of patients and is the rarest translocation of the major five. It results in up regulation of the MAF gene paralog MAFB. According to microarray studies, MAFB overexpression results in a similar gene expression profile (GEP) as that seen with c-MAF [11], implying common downstream targets including CCND2. The translocation is associated with a poor prognosis when present in MM but interestingly correlates to long-term stable disease when found in precursor conditions like MGUS and smoldering MM (SMM) [28]. This suggests that the translocation itself is not responsible for the poor prognosis but additional genetic events are likely required to accumulate imparting this negative prognosis.

MYC translocations have been recently identified in a cohort of 463 whole exome sequencing including extra baits on the MYC locus. MYC translocations were found in 85 patients (18.4 %). Partner genes include IGH, IGL and IGK loci, as well as FAM46C, FOXO3, BMP6 and rarely XBP1, TXNDC5, CCND1, and CCND3. These translocations lead to significant overexpression of MYC, probably resulting from juxtaposition of super-enhancers surrounding the partner gene to MYC locus. MYC translocations are associated with a poor outcome [25].

4 Hyperdiploidy

Hyperdiploidy (HRD) is defined as a number of chromosomes between 48 and 74. HRD MM are characterized by multiple chromosomal gains, preferentially trisomy of chromosomes 3, 5, 7, 9, 11, 15, 19, and 21 [29]. The mechanism underlying this is not known but one hypothesis suggests that the gain of multiple whole chromosomes occurs during a single catastrophic mitosis rather than through the serial gain of chromosomes over time [30]. Nearly half of MGUS and MM tumors are hyperdiploid. Only a few HRD tumors have a co-existing primary IgH translocation—about 10 % of the cases—whereas non-HRD tumors usually have an IgH translocation [31]. Interestingly, in case with coexistent HRD and IGH translocations, HRD may precede IGH translocations in a proportion of patients, as revealed by single-cell sequencing analysis [32]. In terms of signaling pathways, HRD tumors display biological heterogeneity. Some harbor high expression of proliferation-associated genes while others are characterized by genes involved in tumor necrosis factor/nuclear factor-κB (TNF/NFκB) signaling pathway [33]. HRD is associated with a more favorable outcome in general [34], however, coexistent adverse cytogenetic lesions (del 17p, t(4;14) and gain of 1q) shorten survival in MM patients with HDR tumors [32].

5 Copy Number Variations

Copy number variations (CNVs) represent a common feature of MM and are thought to be secondary events, involved in tumor progression. CNVs result from gain and loss of DNA at both a focal level or of an entire chromosome arm. Similarly to single nucleotide mutations, CNVs are probably both driver and passenger events. Highly frequent and recurrent CNVs are likely to be driver, suggesting that the minimal amplified or deleted regions contain important genes involved in the development and progression of MM [35, 36, 37, 38, 39].

1q Gain: Duplication of the long arm of chromosome 1 is present in 35–40 % of patients [36, 40, 41, 42, 43]. This is known to have an adverse effect on overall survival [44]. Gain of 1q21, detected with a specific probe for CKS1B, is an independent prognostic factor and remains when other adverse cytogenetic lesions that frequently coexist are removed [36, 44]. Though the relevant genes on 1q have not yet been fully explored, a minimally amplified region was identified between 1q21.1 and 1q23.3 containing 679 genes. Among these candidate oncogenes are CKS1B, ANP32E, BCL9, and PDZK1 [36, 44, 45]. Of these genes, ANP32E, a protein phosphatase 2A inhibitor involved in chromatin remodeling and transcriptional regulation is of particular interest and has been shown to be independently associated with shortened survival [36]. These findings reinforce the role of gain of 1q in MM pathogenesis and suggest that patients with this type of CNV may benefit from specific inhibitors of these candidate genes and pathways that have been identified.

1p Deletion: Deletions of 1p are observed in approximately 30 % of MM patients and are associated with poor prognosis [36, 46, 47]. Two regions of the 1p arm are of interest in MM pathogenesis when deleted: 1p12 and 1p32.3. 1p12 contains the candidate tumor suppressor gene FAM46C whose expression has been correlated to that of ribosomal proteins and eukaryotic initiation/elongation factors involved in protein translation [48]. This gene has been shown to be frequently mutated in MM and has been independently correlated with a poor prognosis [36, 42, 46, 48]. Region 1p32.3 may be hemi- and homozygously deleted and contains the two target genes CDKN2C and FAF1. CDKN2C is a cyclin-dependent kinase 4 inhibitor involved in negative regulation of the cell cycle, whereas FAF1 encodes a protein involved in initiation and enhancement of apoptosis through the Fas pathway. Deletion 1p is associated with adverse overall survival [49].

13q Deletion: Monosomy of the long arm of chromosome 13 is present in about 45–50 % of patients and is commonly associated with nonhyperdiploid tumors [24, 50, 51, 52]. In approximately 85 % of cases, deletion of chromosome 13 constitutes a monosomy or loss of the q arm, whereas in the remaining 15 % various interstitial deletions occur [50, 53]. Chromosome 13 has been extensively investigated as a prognostic factor and as a location of tumor suppressor genes. The minimally deleted region lies between 13q14.11–13q14.3 and contains 68 genes including RB1, EBPL, RNASEH2B, RCBTB2, and the microRNA miR-16-1 and miR-15a [36]. Molecular studies have shown that the tumor suppressor gene RB1 is significantly under expressed in these deletions and may result in inferior negative cell cycle regulation [36]. Establishing the prognostic significance of deletion 13 is challenging because it is frequently associated with other high risk cytogenetic lesions such as t(4;14) [43]. As such, the historic link between deletion 13 and poor prognosis is a surrogate of its association with high-risk lesions.

17p Deletion: Most of chromosome 17 deletions are hemizygous and of the whole p arm, a genetic event observed in around 10 % of newly diagnosed MM cases with the frequency increasing in later stages of the disease [13, 54]. The minimally deleted region includes the tumor suppressor gene TP53. While cases without del(17p) have a rate of TP53 mutation that is <1 %, cases with the deletion show a higher rate of mutation at 25–37 % [55]—suggesting that mono-allelic 17p deletion contributes to the disruption of the remaining allele. The TP53 gene, which has been mapped to 17p13, is known to function as a transcriptional regulator influencing cell cycle arrest, DNA repair, and apoptosis in response to DNA damage. Loss of 17p is associated with an adverse overall survival [36]. The deletion is also linked to an aggressive disease phenotype, a greater degree of extra-medullary disease, and shortened survival [13, 24, 56].

6 Somatic Mutations

The generalization of next-generation sequencing a few years ago has enabled high throughput whole exome sequencing in several cancers, including MM. The frequency of somatic mutations in MM is at the median across cancer types, with an average of 1.6 mutations per Mb, as compare to less than 0.5/Mb in pediatric cancer, such as rhabdoid tumor or Ewing sarcoma, and about 10/Mb in melanoma and lung cancer [57]. In 2011, Chapman et al. reported whole genome sequencing (WGS) of 23 patients and whole exome sequencing (WES) of 16 patients with MM [48]. By comparing sequences from each tumor to its corresponding normal germline sample, researchers were able to identify tumor-specific mutations. Significantly mutated genes included three that were previously reported as being implicated in MM: KRAS, NRAS, and TP53 as well as two newly described genes FAM46C and DIS3.

Several new oncogenic mechanisms were suggested by the pattern of somatic mutations across this data set. Nearly, half the patients showed mutations of genes involved in protein translation. One of these is the DIS3 gene, also known as RRP44, which encodes a highly conserved RNA exonuclease and serves as the catalytic component of the exosome complex involved in regulating the processing and abundance of all RNA species [58, 59]. DIS3 mutations, postulated to be loss of function, cluster in the enzyme’s catalytic pocket and lead to the deregulation of protein translation as an oncogenic mechanism. Another significantly mutated gene, FAM46C, is less well characterized but thought to be functionally related to the regulation of translation.

The same team next reported a massively parallel sequencing of 203 patients with MM—including the 38 patients previously studied [60]. Beyond the five significantly mutated genes previously described, Lohr et al. identified another six significantly mutated genes (BRAF, TRAF3, PRDM1, CYLD, RB1, and ACTG1). Overall in this study, 65 % of the patients had mutations in one or more of the 11 recurrently mutated genes.

Similarly to KRAS and NRAS, BRAF is a known oncogene playing a role in regulating the MAP kinase pathway. Strikingly, mutations in KRAS, NRAS, and BRAF can be both clonal and subclonal. However, if mutations in these genes sometimes coexist in the same tumor, they are almost never simultaneously clonal indicating that they probably rarely occur in the same clone but rather in different subclones. In contrast, KRAS and DIS3 mutations are reported to be often simultaneously clonal and therefore probably co-occurring in the same clone.

TRAF3 and CYLD are part of the NFkB pathway—which is also the case for 9 other mutated genes of significance in this cohort (BTRC, CARD11, IKBKB, MAP3K1, MAP3K14, RIPK4, TLR4, and TNFRSF1A)—reaffirming the central role of the NFkB pathway in MM.

Another significantly mutated gene is PRDM1 (also called BLIMP1), a transcription factor involved in plasma cell differentiation. Loss of function mutations of BLIMP1 occurs in diffuse large B cell lymphoma [61, 62]. The oncogene IRF4, a transcriptional regulator of PRDM1 was also frequently mutated in addition to mutations seen in PRDM1 itself.

Almost concomitantly, Bolli et al. reported a WES and copy number analysis of 84 MM samples [63]. They identified two new recurrently mutated genes, SP140 and LTB. SP140 is a lymphoid restricted homolog of SP100 that encodes a nuclear body protein implicated in antigen response of mature B cells, and is truncated in several cases. LTB, a type II membrane protein of the TNF family involved in lymphoid development, also harbor truncated mutations.

Finally, Boyle et al. reported a WES of 463 patients enrolled in a large UK phase III clinical trial (ASH 2015, abstract #637), bringing the list to 15 significantly mutated genes, comprising KRAS, NRAS, TP53, FAM46C, DIS3, BRAF, HIST1H1E, RB1, EGR1, TRAF3, LTB, CYLD, IFR4, MAX, and FGFR3. Interestingly, mutations in RAS (43 % of the cases) and NFkB (17 % of the cases) are prognostically neutral. In contrast, mutations in CCND1 and the DNA repair pathway (TP53, ATM, ATR, and ZFHX4) are associated with a negative impact on survival in contrast to those in IRF4 and EGR1 that are associated with a favorable overall survival.

The identification of driver mutations in MM holds great promise for personalized medicine, whereby patients with particular mutations would be treated with the appropriate targeted therapy. However, if the mutation is present in only a fraction of the cells, one might doubt whether such targeted therapy would be clinically efficacious.

7 Clonal Heterogeneity in Multiple Myeloma

In addition to the genetic complexity in MM, intra-clonal heterogeneity has emerged as a further level of complexity. Analyzing clonal heterogeneity by WES, Lohr et al. report that most patients harbor at least three detectable subclones with some having as many as seven, thus reaffirming that MM tumors are highly heterogeneous. Their finding that tumors contain on average at least five subclones is even an underestimation of the clonal diversity in MM as their method only allowed for the detection of subclones representing at least 10 % of the entire tumor sample [60].

It has become clear that following disease initiation, the steps necessary for MM development do not occur through a linear fashion but rather via branching, nonlinear pathways as proposed by Darwin in explaining the evolution of species. This idea is based on the notion that mutations occur randomly and are selected and propagated based on the clonal survival advantage that they confer [64, 65]. A phenomenon of parallel evolution whereby independent but not far-related clones might acquire similar mutations conferring important growth or survival advantages. This is revealed in single-cell level studies showing the same genetic pathway (RAS/MAPK) altered more than once within the same tumor but in divergent clones evolving separately [66]. In a series of t(11;14) MM, evidence for the persistence of the earliest MM progenitor cell clone was found with two cases characterized by the presence of a subclone carrying t(11;14) as the sole abnormality validating that this translocation is an early event in myeloma pathogenesis [66]. The clonal diversity is present at all the stages of the disease. Although less genetically complex than MM, the premalignant stages MGUS and SMM harbor clonal heterogeneity [67]. By studying sequential samples of SMM and overt MM, it was shown that the predominant clone of MM is already present at the SMM stage.

8 Conclusion

MM is genetically complex and heterogeneous disease, combining primary events, secondary events and clonal diversity, leading to tumor development and progression from MGUS to late stages of MM. It is likely that many driver events need to co-occur for MM development and progression. This genomic complexity is a challenge toward the cure of MM. In the past few years, a tremendous amount of information has been revealed by next-generation sequencing of MM tumors. If we have at present a good comprehension of the genomic landscape in MM at presentation, the near future should provide some insights regarding premalignant stages and resistance to treatment.


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Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Salomon Manier
    • 1
    • 2
  • Karma Salem
    • 1
  • Siobhan V. Glavey
    • 1
  • Aldo M. Roccaro
    • 1
    • 3
  • Irene M. Ghobrial
    • 1
  1. 1.Medical Oncology, Dana-Farber Cancer InstituteHarvard Medical SchoolBostonUSA
  2. 2.Department of HematologyLille Hospital UniversityLilleFrance
  3. 3.Department of Hematology, CREA LaboratoryASST-Spedali Civili di BresciaBresciaItaly

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