Chromosome microarray characterisation of chromosome arm 12p loss associated with complex molecular karyotype and recurrent adverse cytogenetic markers in multiple myeloma

Multiple myeloma (MM), a plasma cell neoplasm, is an incurable hematological malignancy characterized by complex genetic and prognostic heterogeneity. Gain or amplification of chromosome arm 1q21 (1q21+) is the most frequent adverse chromosomal aberration in MM, occurring in 40% of patients at diagnosis. It occurs in a subclone of the tumor as a secondary genomic event and is more amplified as the tumor progresses and a risk factor for the progression from smoldering multiple myeloma to MM. It can be divided into either 1q21 gain (3 copies) or 1q21 amplification (≥4 copies), and it has been suggested that the prognosis is worse in cases of amplification than gain. Trisomy of chromosome 1, jumping whole-arm translocations of chromosome1q, and tandem duplications lead to 1q21+ suggesting that its occurrence is not consistent at the genomic level. Many studies have reported that genes associated with the malignant phenotype of MM are situated on the 1q21 amplicon, including CKS1B, PSMD4, MCL1, ANP32E, and others. In this paper, we review the current knowledge regarding the clinical features, prognostic implications, and the speculated pathology of 1q21+ in MM, which can provide clues for an effective treatment approach to MM patients with 1q21+.

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Gains on Chromosome Arm 9q Represent a Novel and Independent Marker of Adverse Prognosis in Multiple Myeloma Patients Receiving Upfront High-Dose Chemotherapy and Autologous Stem Cell Transplantation.

Blood ◽

10.1182/blood.v106.11.1559.1559 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1559-1559

Author(s):

Peter Liebisch ◽

Axel Benner ◽

Kathrin Tschajka ◽

Christiane Wendl ◽

Hartmut Goldschmidt ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Prognostic Markers ◽

Multivariable Analysis ◽

High Dose Chemotherapy ◽

High Dose ◽

Malignant Plasma Cell ◽

Plasma Cell Disorders ◽

Chromosome Arm ◽

Independent Marker

Abstract Introduction: Genomic aberrations represent important prognostic markers in many hematological cancers. In multiple myeloma (MM), chromosome 13q and 17p deletions (13q−, 17p−) have emerged as important outcome predictors that indicate a dismal prognosis. Other chromosomal abnormalities have been discussed as prognostic markers in this disease but came not out as independent variables when they were tested in a multivariable fashion. However, the complexity of genomic rearrangements and the clinical heterogeneity seen in malignant plasma cell disorders argue against 13q− and 17p− as the sole genomic change of prognostic relevance. The significance of chromosome arm 1q, 9q, and 11q extra copies - three frequent genomic imbalances in MM - is undetermined. Material and Methods: 90 patients (pts.) treated with one or two cycles of high-dose chemotherapy (HD-CTX) followed by autologous stem cell transplantation (ASCT) at a single center were analyzed by tri-color FISH and five DNA probes mapping to chromosome bands 1q21, 9q34, 11q25, 13q14, and 17p13. A multivariable analysis (Cox proportional hazards regression model) including genetic and clinical variables was performed. Results: The most frequent aberrations in the present series were (in order of decreasing prevalence): +1q (n=39/78, 50.0%), +9q (n=38/78, 48.7%), 13q− (n=42/90, 46.6%), and +11q (n=39/85, 45.9%). 17p− was identified in only 3 out of 88 patients (3.4%), while +17p were present in 13 out of 88 patients (14.8%). The median follow-up time was 37 months (m) and the median event free survival (EFS) and overall survival (OS) time from first ASCT of the entire cohort was 26 m and 71 m, respectively. Multivariable analysis including genetic aberrations, ß2-microblobulin, albumin, LDH, Salmon/Durie stage, and age at time of diagnosis revealed +9q and 13q− as the only independent predictors of EFS (p=0.003 and p=0.01, respectively). The mEFS in patients with 13q− was 19.0 m and 20.7 m in patients with +9q. In patients with concurrent +9q and 13q−, mEFS was only 12.2 m. In patients lacking these two abnormalities, mEFS was not reached. OS was not significantly influenced by any genetic or clinical variable in our series, most likely due to effective salvage treatment after relapse. Conclusions: +9q represents a novel and independent marker of adverse prognosis in MM. A single FISH experiment applying two DNA probes allows easy and rapid assessment of outcome in patients with malignant plasma cell disorders.

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Gain of chromosome arm 1q in patieznts in relapse and progression of multiple myeloma

Cancer Genetics and Cytogenetics ◽

10.1016/j.cancergencyto.2009.02.020 ◽

2009 ◽

Vol 192 (2) ◽

pp. 68-72 ◽

Cited By ~ 6

Author(s):

Jana Balcárková ◽

Helena Urbánková ◽

Vlastimil Ščudla ◽

Milena Holzerová ◽

Jaroslav Bačovský ◽

...

Keyword(s):

Multiple Myeloma ◽

Chromosome Arm

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Clinically significant recurrent copy number changes detected by chromosome microarray in the CHW multiple myeloma patient cohort

Pathology ◽

10.1016/j.pathol.2016.12.074 ◽

2017 ◽

Vol 49 ◽

pp. S31

Author(s):

Dorothy Hung ◽

Ian Bilmon ◽

Samantha Day ◽

Renee Eslick ◽

David Gottlieb ◽

...

Keyword(s):

Multiple Myeloma ◽

Copy Number ◽

Myeloma Patient ◽

Multiple Myeloma Patient ◽

Patient Cohort ◽

Clinically Significant ◽

Copy Number Changes ◽

Chromosome Microarray

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The Genomic Complexity of Multiple Myeloma Precursor Disease Can be Predicted Using Copy Number Signatures on Targeted Sequencing and SNP Array Data

Blood ◽

10.1182/blood-2020-139879 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 10-10

Author(s):

Kylee H Maclachlan ◽

Binbin Zheng-Lin ◽

Venkata Yellapantula ◽

Even H Rustad ◽

Benjamin Diamond ◽

...

Keyword(s):

Multiple Myeloma ◽

Clinical Trials ◽

Copy Number ◽

Research Funding ◽

Snp Array ◽

Targeted Sequencing ◽

Data Monitoring ◽

Independent Data ◽

Genetics Research ◽

Chromosome Arm

Introduction Current clinical models for predicting the progression from myeloma precursor disease (smoldering multiple myeloma (SMM) and monoclonal gammopathy of undetermined significance (MGUS)) to multiple myeloma (MM) are based on tumor burden, and not designed to capture heterogeneity in tumor biology. With the advent of whole genome sequencing (WGS), complex genomic change including the catastrophic event of chromothripsis has been detected in a significant fraction of MM patients. Chromothripsis is associated with other features of aggressive biology (i.e. biallelic TP53 deletion and increased APOBEC activity), and in newly diagnosed MM (NDMM), patients harboring chromothripsis have a shorter progression free survival (PFS) (Rustad BioRxiv 2019). Chromothripsis has also been demonstrated in SMM which later progressed to MM (Maura Nat Comm 2019) and our preliminary results indicate that the absence of chromothripsis is associated with stable precursor disease (Oben ASH 2020). We have demonstrated that chromothripsis can be accurately predicted in NDMM using copy-number variation (CNV) signatures on both WGS and whole exome sequencing (Maclachlan ASH 2020). As with WGS, CNV signature analysis in less comprehensive assays (e.g. targeted sequencing panels and single nucleotide polymorphism (SNP) arrays) demonstrated that chromothripsis-associated CNV signatures are associated with shorter PFS. The aim of this study was to define the landscape of CNV signatures in myeloma precursor disease, and to compare the results with CNV signatures in NDMM. Methods CNV signature analysis uses 6 fundamental features: i) breakpoint count per 10 Mb, ii) absolute CN of segments, iii) difference in CN between adjacent segments, iv) breakpoint count per chromosome arm, v) lengths of oscillating CN segments, and vi) the size of segments (Macintyre Nat Gen 2018). The number of subcategories for each feature (which may differ between cancer and assay types) was established using a mixed effect model (mclust R package). For both targeted sequencing (myTYPE panel; (n=19, 4 MGUS, 15 SMM) and SNP array (n=78, 16 MGUS, 62 SMM), de novo CNV signature extraction was performed by hierarchical dirichlet process, running the analysis together with NDMM samples for reliable signature detection. Results Our analysis identified 4 and 6 CNV signatures from myTYPE and SNP array data respectively, with the extracted signatures being analogous to those from WGS, which are highly predictive of chromothripsis (Maclachlan ASH 2020). Compared with NDMM (myTYPE; n=113; SNP array; n=217), precursor samples contained significantly fewer breakpoints / chromosome arm (myTYPE; p= 0.0003, SNP; p <0.0001), fewer breakpoints / 10 Mb (both; p <0.0001), shorter lengths of oscillating CN (myTYPE; p= 0.013, SNP; p= 0.018), fewer jumps between CN states (myTYPE; p= 0.0043, SNP; p < 0.0001), lower absolute CN (myTYPE; p= 0.0059, SNP; p < 0.0001) and fewer small segments of CN change (myTYPE; p= 0.0007, SNP; p= 0.0008). Chromothripsis-associated CNV signatures were significantly enriched in NDMM compared to precursor disease (p<0.0001), with only 8.2% of precursors having a significant contribution from these signatures (NDMM; 38.7%). Overall, every CNV feature consistent with chromothripsis was measured at a significantly lower level in precursors than NDMM. As <5% of the precursors have progressed to MM, and given that we see heterogeneity in the pattern of CNV abnormalities both between MM and precursor disease, and within patients with precursor disease, we are currently investigating the role of CNV abnormalities in relation to clinical progression. As an interim measure; restricting analysis to patients with clinical stability >5 years (n=11), we observed chromothripsis-associated signatures to be absent in all samples. Conclusion All individual CN features comprising chromothripsis-associated CNV signatures are significantly lower in stable myeloma precursor disease compared with NDMM when assessed by targeted sequencing and SNP array, along with a lower contribution from chromothripsis-associated signatures. Given the adverse impact of chromothripsis in MM, these data show great promise towards the future refinement of risk prediction estimation in myeloma precursor disease. Our ongoing work involves extending CNV analysis into larger datasets, including precursor patients who subsequently progressed to MM. Disclosures Hultcrantz: Intellisphere LLC: Consultancy; Amgen: Research Funding; Daiichi Sankyo: Research Funding; GSK: Research Funding. Dogan:Roche: Consultancy, Research Funding; Physicians Education Resource: Consultancy; Corvus Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Takeda: Consultancy; EUSA Pharma: Consultancy; AbbVie: Consultancy; National Cancer Institute: Research Funding. Morgan:Bristol-Myers Squibb: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; GSK: Consultancy, Honoraria. Landgren:Amgen: Consultancy, Honoraria, Research Funding; Karyopharma: Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Seattle Genetics: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Glenmark: Consultancy, Honoraria, Research Funding; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Cellectis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Binding Site: Consultancy, Honoraria; Adaptive: Consultancy, Honoraria; Merck: Other; Pfizer: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Binding Site: Consultancy, Honoraria; Karyopharma: Research Funding; Merck: Other; Pfizer: Consultancy, Honoraria; Seattle Genetics: Research Funding; Juno: Consultancy, Honoraria; Glenmark: Consultancy, Honoraria, Research Funding.

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Genomic instability in multiple myeloma: Evidence for jumping segmental duplications of chromosome arm 1q

Genes Chromosomes and Cancer ◽

10.1002/gcc.20109 ◽

2004 ◽

Vol 42 (1) ◽

pp. 95-106 ◽

Cited By ~ 62

Author(s):

Jeffrey R. Sawyer ◽

Guido Tricot ◽

Janet L. Lukacs ◽

Regina Lichti Binz ◽

Erming Tian ◽

...

Keyword(s):

Multiple Myeloma ◽

Genomic Instability ◽

Segmental Duplications ◽

Chromosome Arm

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A Novel Mechanism for Intrachromosomal Gene Amplification in Multiple Myeloma: 1q12 Pericentromeric Heterochromatin Mediates Breakage- Fusion-Bridge Cycles of the 1q12~23 Amplicon

Blood ◽

10.1182/blood.v112.11.493.493 ◽

2008 ◽

Vol 112 (11) ◽

pp. 493-493

Author(s):

Jeffrey Sawyer ◽

Erming Tian ◽

Edward Thomas ◽

Mark Koller ◽

Collin Stangeby ◽

...

Keyword(s):

Multiple Myeloma ◽

Gene Amplification ◽

Fragile Site ◽

Pericentromeric Region ◽

Chromosome Breakage ◽

Pericentromeric Heterochromatin ◽

Metaphase Chromosomes ◽

Site Specific ◽

Chromosome Arm ◽

Bfb Cycle

Abstract Gene amplification is a marked copy number (CN) increase in a restricted region of a chromosome arm, and is a mechanism for acquired drug resistance and oncogene activation. In multiple myeloma (MM), recent studies utilizing gene expression profiling, high-resolution array comparative genomic hybridization (aCGH), and global single nucleotide polymorphism arrays have all provided molecular evidence for the importance of genes in the proximal 1q. In fact, the aCGH studies have defined a particularly notable region of proximal 1q with a marked enrichment of genes which spans approximately 143–158 Mb corresponding to a 1q21-23 amplicon. The finding of high CNs of CKS1B and other genes in the 1q21~23 amplicon have been associated with disease progression and poor prognosis in MM. To investigate the possible mechanisms for focal gene amplification in this region, we identified 70 patients showing gain of 1q by G-banding. We then performed a comprehensive metaphase analysis utilizing fluorescence in situ hybridization (FISH) and spectral karyotyping to further characterize the karyotypic aberrations. Six FISH probes spanning the 1q12~23 region were used, including among others, probes for satII/III at 1q12 in the pericentromeric region to demark a proximal boundary, CKS1B at 1q21 to demark a point near the center of the amplicon, and RP11-57D16 at 1q25.2 to demark a distal boundary. In seven patients (10%) evidence for at least one breakage-fusion-bridge (BFB) cycle involving 1q12~23 in an inverted duplication was found. Strikingly, in three patients (4%) extended ladder-like structures of 1q12~23 inverted duplications were identified with up to 18 copies of CKS1B in contiguous duplicated regions. In these patients, the “amplicon ladders” showed the progression from two, to four, to eight copies, of CKS1B in different cells. Several key structures that are predicted intermediates in BFB cycles were observed in these patients, including equally spaced organization of amplicons, isodicentric chromosomes 1 with a clustering of breakpoints in the duplicated 1q12 pericentromeric regions, inverted repeat organization of amplicons along the same chromosome arm, and deletion of sequences distal to the amplified region. In these patients, site-specific breakage in the 1q12 pericentromeric heterochromatin mediated the organization of the BFB cycles by ultimately bracketing both the proximal and distal boundaries of the amplicon. Two chromosomal mechanisms have been described for the initiation of BFB cycles in tumor cells: the telomere fusion model in which chromosome breakage is induced by shortened or dysfunctional telomeres, and the alternative mechanism whereby replication stress and/or delay induces chromosome breakage in common fragile sites (CFS). The site-specific chromosome breakage in the satII/III sequences in the different phases of the intermediate chromosome structures identified here strongly support the concept that the BFB cycles were initiated by a CFS mechanism. A possible candidate fragile site in the 1q12 pericentromeric region is FRA1J, a known 5-azacytidine fragile site. It is well established that 5-azacytidine is a methyl transferase inhibitor which induces hypomethylation of the 1q12 pericentromeric DNA in metaphase chromosomes resulting in a characteristic pattern of pericentromeric decondensation and chromosome breakage. Our findings provide the first evidence for the BFB cycle mechanism of gene amplification in MM, and that the amplification process is induced by the secondary activation of a CFS in the 1q12 pericentromeric heterochromatin.

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Proteasome inhibitors as therapeutics

Essays in Biochemistry ◽

10.1042/bse0410205 ◽

2005 ◽

Vol 41 ◽

pp. 205-218

Author(s):

Constantine S. Mitsiades ◽

Nicholas Mitsiades ◽

Teru Hideshima ◽

Paul G. Richardson ◽

Kenneth C. Anderson

Keyword(s):

Multiple Myeloma ◽

Drug Class ◽

Proteasome Inhibitors ◽

Cell Cycle Regulators ◽

Current State ◽

Intracellular Mechanism ◽

Ubiquitin Proteasome ◽

Proteasome Pathway ◽

Hodgkin's Lymphomas ◽

Clinical Research Data

The ubiquitin–proteasome pathway is a principle intracellular mechanism for controlled protein degradation and has recently emerged as an attractive target for anticancer therapies, because of the pleiotropic cell-cycle regulators and modulators of apoptosis that are controlled by proteasome function. In this chapter, we review the current state of the field of proteasome inhibitors and their prototypic member, bortezomib, which was recently approved by the U.S. Food and Drug Administration for the treatment of advanced multiple myeloma. Particular emphasis is placed on the pre-clinical research data that became the basis for eventual clinical applications of proteasome inhibitors, an overview of the clinical development of this exciting drug class in multiple myeloma, and a appraisal of possible uses in other haematological malignancies, such non-Hodgkin's lymphomas.

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