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

2004 ◽  
Vol 42 (1) ◽  
pp. 95-106 ◽  
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

scholarly journals Gain/Amplification of Chromosome Arm 1q21 in Multiple Myeloma

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 256
Author(s):  
Ichiro Hanamura
Keyword(s):  
Multiple Myeloma ◽  
Hematological Malignancy ◽  
Treatment Approach ◽  
Current Knowledge ◽  
Chromosome 1 ◽  
Plasma Cell Neoplasm ◽  
Chromosome Arm ◽  
Cell Neoplasm ◽  
Prognostic Implications ◽  
Tandem Duplications

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+.

scholarly journals Telomere Architecture Correlates with Aggressiveness in Multiple Myeloma

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1969
Author(s):  
Aline Rangel-Pozzo ◽  
Pak Yu ◽  
Sadhana LaL ◽  
Yasmin Asbaghi ◽  
Luiza Sisdelli ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Disease Progression ◽  
Genomic Instability ◽  
Clinical Decision Making ◽  
Three Dimensional ◽  
Clinical Decision ◽  
Response To Treatment ◽  
Average Intensity ◽  
Patient Response ◽  
Smoldering Multiple Myeloma

The prognosis of multiple myeloma (MM), an incurable B-cell malignancy, has significantly improved through the introduction of novel therapeutic modalities. Myeloma prognosis is essentially determined by cytogenetics, both at diagnosis and at disease progression. However, for a large cohort of patients, cytogenetic analysis is not always available. In addition, myeloma patients with favorable cytogenetics can display an aggressive clinical course. Therefore, it is necessary to develop additional prognostic and predictive markers for this disease to allow for patient risk stratification and personalized clinical decision-making. Genomic instability is a prominent characteristic in MM, and we have previously shown that the three-dimensional (3D) nuclear organization of telomeres is a marker of both genomic instability and genetic heterogeneity in myeloma. In this study, we compared in a longitudinal prospective study blindly the 3D telomeric profiles from bone marrow samples of 214 initially treatment-naïve patients with either monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or MM, with a minimum follow-up of 5 years. Here, we report distinctive 3D telomeric profiles correlating with disease aggressiveness and patient response to treatment in MM patients, and also distinctive 3D telomeric profiles for disease progression in smoldering multiple myeloma patients. In particular, lower average intensity (telomere length, below 13,500 arbitrary units) and increased number of telomere aggregates are associated with shorter survival and could be used as a prognostic factor to identify high-risk SMM and MM patients.

scholarly journals Comprehensive Analysis of Human Subtelomeres by Whole Genome Mapping

2019 ◽  
Author(s):  
Eleanor Young ◽  
Heba Z. Abid ◽  
Pui-Yan Kwok ◽  
Harold Riethman ◽  
Ming Xiao
Keyword(s):  
Long Range ◽  
Genome Mapping ◽  
Subtelomeric Region ◽  
Reference Sequence ◽  
Segmental Duplications ◽  
Structural Variations ◽  
Sequence Characterization ◽  
Current Reference ◽  
Sequencing Technologies ◽  
Chromosome Arm

AbstractDetailed comprehensive knowledge of the structures of individual long-range telomere-terminal haplotypes are needed to understand their impact on telomere function, and to delineate the population structure and evolution of subtelomere regions. However, the abundance of large evolutionarily recent segmental duplications and high levels of large structural variations have complicated both the mapping and sequence characterization of human subtelomere regions. Here, we use high throughput optical mapping of large single DNA molecules in nanochannel arrays for 154 human genomes from 26 populations to present a comprehensive look at human subtelomere structure and variation. The results catalog many novel long-range subtelomere haplotypes and determine the frequencies and contexts of specific subtelomeric duplicons on each chromosome arm, helping to clarify the currently ambiguous nature of many specific subtelomere structures as represented in the current reference sequence (HG38). The organization and content of some duplicons in subtelomeres appear to show both chromosome arm and population-specific trends. Based upon these trends we estimate a timeline for the spread of these duplication blocks.Author SummaryThe ends of human chromosomes have caps called telomeres that are essential. These telomeres are influenced by the portions of DNA next to them, a region known as the subtelomere. We need to better understand the subtelomeric region to understand how it impacts the telomeres. This subtelomeric region is not well described in the current references. This is due to large variations in this region and portions that are repeated many times, making current sequencing technologies struggle to capture these regions. Many of these variations are evolutionary recent. Here we use 154 different samples from the 26 geographic regions of the world to gain a better understanding of the variation in these regions. We found many new haplotypes and clarified the haplotypes existing in the current reference. We then examined population and chromosome specific trends.

scholarly journals PDZ Binding Kinase (PBK) - a Novel Gene Driving Genomic Evolution in Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4474-4474
Author(s):  
Subodh Kumar ◽  
Leutz Buon ◽  
Srikanth Talluri ◽  
Jialan Shi ◽  
Hervé Avet-Loiseau ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Genomic Instability ◽  
Cell Lines ◽  
Excision Repair ◽  
Critical Role ◽  
Micronucleus Assay ◽  
Genomic Evolution ◽  
Dna Breaks ◽  
Functional Changes ◽  
Elevated Expression

Abstract As in all cancers, genomic instability leads to ongoing acquisition of new genetic changes in multiple myeloma (MM). This adaptability underlies the development of drug resistance and progression in MM. This genomic instability is driven by cellular processes, mainly related with DNA repair and perturbed by functional changes in limited number of genes. Since kinases play a critical role in the regulation of biological processes, including DNA damage/repair signaling and are relatively easy to screen for inhibitors, we investigated for novel genes involved in the acquisition of new genomic changes in MM. Using a large genomic database which had both the gene expression and CGH array-based copy number information (gse26863, n=246), we first identified a total of 890 expressed kinases in MM and correlated their expression with genomic instability defined as a change in ≥3 and/or 5 consecutive amplification and/or deletion events. We identified 198 kinases whose elevated expression correlated with increased genomic instability (based on FDR ≤ 0.05). Amongst these kinases, using univariate Cox survival analysis, elevated expression of 15 kinases correlated with poor overall as well as event free survival (P ≤0.05) in two MM datasets (IFM70, n=170; gse24080; n=559). We further confirmed the correlation of these 15 genes in both EFS and OS in additional two MM datasets (MMRF CoMMpass Study, IFM-DFCI 2009) as well as in additional solid tumor datasets from TCGA from patients with lung and pancreatic adenocarcinoma (P values ranging from 0.01 to <0.000002). A pathway analysis identified phosphorylation and regulation of proteasome pathway, mitotic spindle assembly/checkpoint, chromosomal segregation and cell cycle checkpoints as among major pathways regulated by these genes. To investigate the relevance of these genes with genomic instability, we performed a functional siRNA screen to evaluate impact of their suppression on homologous recombination (HR). PDZ Binding Kinase (PBK) was one of the top genes whose knockdown caused the maximal inhibition of HR activity in initial screen. To investigate it further in detail, we suppressed PBK in MM cells using shRNA and confirmed that its suppression significantly reduces HR activity. PBK-knockdown also reduced gH2AX levels (marker of DNA breaks) measured by Western blotting and decreased number of micronuclei (a marker of ongoing genomic rearrangements and instability) as assessed by flow cytometry . A small molecule inhibitor of PBK also confirmed a similar reduction in gH2AX levels as well as micronuclei, indicating inhibition of spontaneous DNA breaks and genomic instability. Using mass spectrometry and co-immunoprecipitation, we identified that PBK interacts with FEN1, a nuclease with roles in base excision repair and HR pathways. We confirmed that PBK induces phosphorylation of FEN1 and that inhibition of PBK, suppressed the phosphorylation of FEN1, RAD51 expression and gH2AX levels and it reversed FEN1-induced HR activity. These results confirm that phosphorylation of FEN1 nuclease by PBK contributes to its ability to impact DNA breaks, HR and genome stability in MM. PBK inhibition also significantly sensitized MM cells to melphalan and inhibited cell viability in a panel of MM cell lines (IC50 in MM cell lines ~20-30 nM vs ~100 nM in normal PBMCs) at the same time also reversed melphalan-induced genomic instability, as assessed by micronucleus assay. These data identify PBK as an important target affecting genomic instability, and its inhibitor as a potential drug, to inhibit genomic evolution and MM cell growth. Disclosures Munshi: OncoPep: Other: Board of director.

scholarly journals Short tandem repeats, segmental duplications, gene deletion, and genomic instability in a rapidly diversified immune gene family

BMC Genomics ◽  
2016 ◽  
Vol 17 (1) ◽  
Author(s):  
Matan Oren ◽  
Megan A. Barela Hudgell ◽  
Brian D’Allura ◽  
Jacob Agronin ◽  
Alexandra Gross ◽  
...  
Keyword(s):  
Gene Family ◽  
Genomic Instability ◽  
Short Tandem Repeats ◽  
Gene Deletion ◽  
Tandem Repeats ◽  
Immune Gene ◽  
Segmental Duplications ◽  
Short Tandem

scholarly journals The Use of Murine Models for Studying Mechanistic Insights of Genomic Instability in Multiple Myeloma

2019 ◽  
Vol 10 ◽  
Author(s):  
Philip Vlummens ◽  
Kim De Veirman ◽  
Eline Menu ◽  
Elke De Bruyne ◽  
Fritz Offner ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Genomic Instability ◽  
Murine Models

scholarly journals Drug Targeting of Genomic Instability in Multiple Myeloma

2020 ◽  
Vol 11 ◽  
Author(s):  
Meral Beksac ◽  
Sevinc Balli ◽  
Dilara Akcora Yildiz
Keyword(s):  
Multiple Myeloma ◽  
Genomic Instability ◽  
Drug Targeting

Dysregulated Apurinic/Apyrimidinic Endonucleases (Ape1 and Ape2) Lead to Genetic Instability in Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1418-1418
Author(s):  
Masood A. Shammas ◽  
Hemant Koley ◽  
Sima Shah ◽  
Ramesh B. Batchu ◽  
Pierfrancesco Tassone ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Homologous Recombination ◽  
Genomic Instability ◽  
Cell Lines ◽  
Plasma Cells ◽  
Dna Recombination ◽  
Endonuclease Activity ◽  
Single Nucleotide ◽  
Genetic Changes

Abstract Multiple myeloma (MM) is associated with significant genomic instability. Homologous recombination (HR), which is elevated in MM, is considered to be responsible for this instability. As endonucleases play an important role in mediating HR, here we have evaluated the role of endonuclease in biology and progression of MM. Gene expression profile using Affymetrix U133 array showed &gt; 2 fold elevation of Ape1 or Ape2 or both in 5 of 6 MM cell lines and 12 of 15 patient samples. Immunocytochemistry confirmed upregulation of Ape1 protein in MM cell lines. A Plasmid degradation assay confirmed significantly elevated endonuclease activity in MM cells compared to normal plasma cells. To identify the pre-dominating endonuclease activity, the degradation assay was carried out in the presence of specific endonuclease inhibitors. Harmane and methoxyamine (MA), specific inhibitors of apurinic/apyrimidinic endonucleases effectively inhibited significant endonuclease activity, while other endonuclease inhibitors ACPD and FK506 had minimal effects, confirming predominant role of apurinic/apyrimidinic endonucleases (APE) in mediating increased endonuclease activity in MM. We investigated the role of elevated APE endonuclease activity on DNA recombination and subsequent genomic re-arrangements. Using a plasmid-based assay we have previously demonstrated significantly elevated homologous recombination (HR) in MM. Inhibition of endonuclease by methoxyamine suppressed HR activity by 85 ± 2% in MM cells. Next, we evaluated whether inhibition of HR by methoxyamine can affect the frequency of acquisition of new genetic changes in MM cells using single nucleotide polymorphism (SNP) arrays (Affymetrix) as indicator of genomic instability. In three independent experiments, methoxyamine reduced the acquisition of new loss of heterozygocity (LOH) loci by an average of 71%. These data suggest that the dysregulated APE endonucleases contribute significantly to the genomic instability, acquisition of new mutations and progression of MM and provides the rationale for targeting endonuclease activity to prevent disease progression including development of drug resistance.

Molecular Basis of Genomic Instability and Progression in Multiple Myeloma: Potential Role of Apurinic (Apyrimidinic) Endonuclease.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1561-1561
Author(s):  
Masood A. Shammas ◽  
Hemanta Koley ◽  
Paola Neri ◽  
Pierfrancesco Tassone ◽  
Ramesh B. Batchu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Genomic Instability ◽  
Cell Lines ◽  
Molecular Basis ◽  
Endonuclease Activity ◽  
Ap Endonuclease ◽  
Myeloma Cells ◽  
Genome Wide ◽  
New Mutations

Abstract Genetic instability is a prominent feature of most cancers including multiple myeloma (MM) and is responsible for ongoing accrual of mutational changes which may lead to development of drug resistance and metastasis. The molecular basis for the generation of genetic diversity in MM is therefore extremely important to understand carcinogenesis and to identify novel targets for treatment. As genomic rearrangements require excision of DNA, we hypothesized that an elevated endonuclease activity may induce recombination and subsequent genomic instability in cancer cells. We developed a plasmid degradation assay that confirmed significantly elevated endonuclease activity in MM cells compared to normal plasma cells. To identify the pre-dominating endonuclease the degradation assay was carried out in the presence of specific endonuclease inhibitors, which identified apurinic/apyrimidinic endonuclease (Ape1 and Ape2) as the predominant endonucleases in mediating increased endonuclease activity in MM. Gene expression analysis confirmed &gt; 2 fold elevation of Ape1 or Ape2 or both in 5 of 6 MM cell lines and 12 of 15 patient samples. Both immunocytochemistry and western blot analyses confirmed upregulation of Ape1 protein in all MM cell lines and patient samples. Next, we investigated the role of elevated APE endonuclease activity in DNA recombination and subsequent genomic re-arrangements. Using a plasmid-based assay we have previously demonstrated significantly elevated homologous recombination (HR) in MM. To investigate the role of elevated AP endonuclease activity in MM, we cultured myeloma cells in the presence of methoxyamine (MX), which specifically inhibits AP endonuclease activity, and evaluated its effect on HR activity and genome-wide appearance of new mutations. Exposure of intact myeloma cells to MX resulted in &gt; 90% inhibition of HR activity and a significant (71±10.9%; p&lt;0.05) reduction in the appearance of new mutations compared to untreated cells, as assessed by genome-wide loss of heterozygosity (LOH) assay (Affymetrix). We also evaluated the effects of overexpression of Ape1 & 2 in normal fibroblasts which have low endonuclease activity. The transgenic upregulation of AP endonucleases (Ape1 and Ape2) in normal cells led to a significant increase in the lecombination activity, leading to a marked mutational instability as indicated by the appearance of over 20,063 and 20,143 new LOH loci per 100,000 polymorphic regions examined throughout the genome, at population doublings 25 and 50 respectively. Mutational instability was also associated with chromosomal instability confirmed by spectral karyotyping of these cells showing significant numerical and structural chromosomal abnormalities. These changes were associated with indefinite growth of cells and formation of tumors when injected in SCID mice. These data suggest that elevated AP endonuclease may be responsible for mutational and chromosomal instabilities, leading to progression of myeloma.

Analysis of genomic DNA copy number alterations in chromosome arm 18q demonstrates distinct molecular categories of colorectal carcinoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10005-10005
Author(s):  
H. Ji ◽  
M. Zhang ◽  
K. Farnam ◽  
K. Salari ◽  
R. Davis ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colorectal Carcinoma ◽  
Genomic Instability ◽  
Genetic Markers ◽  
New Technologies ◽  
Stage Ii ◽  
Cancer Genes ◽  
Genomic Deletions ◽  
Chromosome Arm ◽  
Dna Copy Number Alterations

10005 Background: Genomic instability is a major feature of neoplastic development in colorectal carcinoma and other cancers. Specific genomic instability events such as genomic deletions have potential utility as biologically relevant prognostic biomarkers. Loss of heterozygosity (LOH) on chromosome arm 18q is an indicator of colorectal carcinoma behavior and potentially, prognosis. For stage II and III colorectal cancer, a number of retrospective studies have shown strong correlations between deletions in 18q and reduced survival. However, other studies have failed to identify this correlation. This discrepancy is likely the result of different sets of genetic markers and their widely disparate locations along chromosome arm 18q, often separated by megabases. New technologies are needed to overcome these issues. Methods: Using a novel genomic technology called molecular inversion probes (MIPs), we analyzed genomic deletions at exon-level resolution in primary colorectal carcinoma. Unlike microsatellite genetic markers, MIPs are not dependent on having informative alleles to discern a LOH event. This enables querying microsatellite genetic markers used in any clinical study. We designed a set of probes to interrogate several hundred individual exons of over two hundred cancer genes with an overall distribution covering all chromosome arms. Also represented were a series of over 100 probes along chromosome arm 18q representing genetic markers used in clinical studies. An analysis was carried out on primary tumor samples from patients with stage II and III disease. Results: We discovered several distinct categories of colorectal carcinomas based upon their profile of 18q genomic deletions and other allelic imbalances. Colorectal carcinoma extent of invasion showed an association with cluster designation which suggests that the multiple genomic instability events influence the invasive behavior of colorectal carcinoma. Conclusions: Colorectal cancer has distinct patterns of 18q genomic deletions, representing a potential molecular classifier. This finding has potential clinical ramifications given the application of 18q LOH events as an indicator for adjuvant treatment in stage II colorectal carcinoma. No significant financial relationships to disclose.

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