Occurrence and prognostic significance of cytogenetic evolution in patients with multiple myeloma.
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ABSTRACT:
SUBMITTER: Binder M
PROVIDER: S-EPMC4817098 | biostudies-other | 2016 Mar
REPOSITORIES: biostudies-other
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Project description:We investigated subclonal cytogenetic aberrations (CA) detected by interphase fluorescence in situ hybridization (iFISH) in patients with newly diagnosed multiple myeloma (MM) enrolled in the Haemato Oncology Foundation for Adults in the Netherlands (HOVON)-65/German-Speaking MM Group (GMMG)-HD4 phase 3 trial. Patients were either treated with 3 cycles of vincristine, Adriamycin, and dexamethasone or bortezomib, Adriamycin, and dexamethasone and then thalidomide or bortezomib maintenance after tandem autologous transplantation. Subclones were defined either by presence of different copy numbers of the same chromosome loci and/or CA present in at least 30% less and maximally 2/3 of cells compared with the main clone CA. Patients with subclones harbored more frequently high risk (31.0%) or hyperdiploid main clone aberrations (24.8%) than patients with t(11;14) in the main clone (10.1%). Gains and deletions of c-MYC were the only CA that occurred more frequently as subclone (8.1%/20.5%) than main clone (6.2%/3.9%, respectively). Treatment with bortezomib completely overcame the negative prognosis of high-risk CA in patients without subclones, but not in patients with additional subclonal CA. High-risk patients treated without bortezomib showed dismal outcome whether subclones were present or not. Cytogenetic heterogeneity defined by subclonal CA is of major prognostic significance in newly diagnosed MM patients treated with bortezomib within the HOVON-65/GMMG-HD4 trial.
| S-EPMC5761630 | biostudies-literature
Project description:The identification of specific cytogenetic abnormalities by interphase fluorescence in situ hybridization (i-FISH) has become a routine procedure for prognostic stratification of multiple myeloma (MM) patients. In this study, the prognostic significance of cytogenetic abnormalities detected by interphase fluorescence in situ hybridization (iFISH) in 229 newly diagnosed multiple myeloma patients was retrospectively analyzed. Results showed that del (17p), t(4;14), and 1q21 gain were adverse predictors of progression-free survival (PFS). Patients who carried these cytogenetic abnormalities were more likely to have more adverse biological parameters and lower response rate. Multivariate analysis showed that del (17p), t(4;14), and 1q21 gain were statistically independent predictors of PFS, whereas del (17p) was also adverse predictor of overall survival. Multiple coexisting cytogenetic abnormalities also had a negative correlation with PFS. Bortezomib-based therapy could improve the rate and depth of response in patients with t(4;14) translocation and 1q21 gain. Autologous stem cell transplantation could improve, but not overcome the adverse prognostic effect of high-risk cytogenetic abnormalities. These results demonstrate that MM patients with iFISH abnormalities, especially del (17p), are more likely to have a poor prognosis.
| S-EPMC4902489 | biostudies-literature
Project description: Not available
| S-EPMC7214236 | biostudies-literature
Project description:Purpose Chromosomal aberrations are a hallmark of multiple myeloma but their global prognostic impact is largely unknown. Methods We performed a genome-wide analysis of malignant plasma cells from 192 newly myeloma patients using high-density, single-nucleotide polymorphism (SNP) arrays to identify genetic lesions associated with prognosis. Results Our analyses revealed deletions and amplifications in 98% of cases. Amplifications in 1q and deletions in 1p, 12p, 14q, 16q, and 22q were the most frequent lesions associated with adverse prognosis while recurrent amplifications of chromosomes 5, 9, 11, 15 and 19 conferred a favorable prognosis. Multivariate analysis retained three independent lesions: amp(1q23.3), amp(5q31.3) and del(12p13.31). When adjusted to the established prognostic variables ie t(4;14), and serum beta2-microglobulin (Sb2M), del(12p13.31) remained the most powerful independent marker (P <.0001; hazard ratio = 3.17) followed by Sb2M (P <.0001; hazard ratio = 2.78) and amp(5q31.3) (P =.0005; hazard ratio = 0.37). Cases with amp(5q31.3) alone and low Sb2M had an excellent prognosis (5-year overall survival = 87%) conversely cases with del(12p13.31) alone or amp(5q31.3) and del(12p13.31) and high Sb2M had a very poor outcome (5-year overall survival = 20%). Moreover, integration of SNP mapping and gene expression identified CD27 as potential critical gene responsible for poor prognosis of del(12p) myeloma patients. Conclusion These findings demonstrate the power and accessibility of molecular karyotyping to identify novel strong independent prognostic markers: amp(5q31.3) and del(12p13.31) and to provide insights into putative pathways deregulated in sub classes of cancer patients. Keywords: Human chromosome copy-number alterations study
2009-08-20 | GSE12896 | GEO
Project description:Purpose Chromosomal aberrations are a hallmark of multiple myeloma but their global prognostic impact is largely unknown. Methods We performed a genome-wide analysis of malignant plasma cells from 192 newly myeloma patients using high-density, single-nucleotide polymorphism (SNP) arrays to identify genetic lesions associated with prognosis. Results Our analyses revealed deletions and amplifications in 98% of cases. Amplifications in 1q and deletions in 1p, 12p, 14q, 16q, and 22q were the most frequent lesions associated with adverse prognosis while recurrent amplifications of chromosomes 5, 9, 11, 15 and 19 conferred a favorable prognosis. Multivariate analysis retained three independent lesions: amp(1q23.3), amp(5q31.3) and del(12p13.31). When adjusted to the established prognostic variables ie t(4;14), and serum beta2-microglobulin (Sb2M), del(12p13.31) remained the most powerful independent marker (P <.0001; hazard ratio = 3.17) followed by Sb2M (P <.0001; hazard ratio = 2.78) and amp(5q31.3) (P =.0005; hazard ratio = 0.37). Cases with amp(5q31.3) alone and low Sb2M had an excellent prognosis (5-year overall survival = 87%) conversely cases with del(12p13.31) alone or amp(5q31.3) and del(12p13.31) and high Sb2M had a very poor outcome (5-year overall survival = 20%). Moreover, integration of SNP mapping and gene expression identified CD27 as potential critical gene responsible for poor prognosis of del(12p) myeloma patients. Conclusion These findings demonstrate the power and accessibility of molecular karyotyping to identify novel strong independent prognostic markers: amp(5q31.3) and del(12p13.31) and to provide insights into putative pathways deregulated in sub classes of cancer patients. Keywords: Human chromosome copy-number alterations study 192 myeloma patients at diagnosis examined with 500K Set Affymetrix chips
2009-08-19 | E-GEOD-12896 | biostudies-arrayexpress
Project description:BACKGROUND:Multiple myeloma (MM) is the plasma cell tumor, which is characterized by clonal proliferation of tumor cells, with high risk of progression to renal impairment, bone damage and amyloidosis. Although the survival rate of patients with MM has improved in the past decade, most people inevitably relapse. The treatment and prognosis of MM are still urgent problems. Breast Cancer Antiestrogen Resistance 3 (BCAR3) is a protein-coding gene that is associated with many tumors. However, there have been few studies on the relationship of BCAR3 and MM. METHODS:We analyzed 1878 MM patients (1930 samples) from 7 independent datasets. First, we compared the BCAR3 expression level of MM patients in different stages and MM patients with different amplification of 1q21. Second, we analyzed BCAR3 expression levels in MM patients with different molecular subtypes. Finally, we explored the event-free survival rate (EFS) and overall survival rate (OS) of MM patients with high or low BCAR3 expression, including patients before and after relapse, and their therapeutic responses to bortezomib and dexamethasone. RESULTS:The expression of BCAR3 showed a decreasing trend in stages I, II and III (P?=?0.00068). With the increase of 1q21 amplification level, the expression of BCAR3 decreased (P?=?0.022). Patients with high BCAR3 expression had higher EFS and OS (EFS: P?<?0.0001, OS: P?<?0.0001). The expression of BCAR3 gene before relapse was higher than that after relapse (P?=?0.0045). BCAR3 is an independent factor affecting prognosis (EFS: P?=?5.17E-03; OS: P?=?3.33E-04). CONCLUSION:We found that high expression level of BCAR3 predicted better prognosis of MM patients. Low expression of BCAR3 at diagnosis can predict early relapse. BCAR3 is an independent prognostic factor for MM. BCAR3 can be used as a potential biomarker.
| S-EPMC6299524 | biostudies-literature
Project description:PurposeChromosomal aberrations are a hallmark of multiple myeloma but their global prognostic impact is largely unknown.Patients and methodsWe performed a genome-wide analysis of malignant plasma cells from 192 newly diagnosed patients with myeloma using high-density, single-nucleotide polymorphism (SNP) arrays to identify genetic lesions associated with prognosis.ResultsOur analyses revealed deletions and amplifications in 98% of patients. Amplifications in 1q and deletions in 1p, 12p, 14q, 16q, and 22q were the most frequent lesions associated with adverse prognosis, whereas recurrent amplifications of chromosomes 5, 9, 11, 15, and 19 conferred a favorable prognosis. Multivariate analysis retained three independent lesions: amp(1q23.3), amp(5q31.3), and del(12p13.31). When adjusted to the established prognostic variables (ie, t(4;14), del(17p), and serum beta(2)-microglobulin [Sbeta(2)M]), del(12p13.31) remained the most powerful independent adverse marker (P < .0001; hazard ratio [HR], 3.17) followed by Sbeta(2)M (P < .0001; HR, 2.78) and the favorable marker amp(5q31.3) (P = .0005; HR, 0.37). Patients with amp(5q31.3) alone and low Sbeta(2)M had an excellent prognosis (5-year overall survival, 87%); conversely, patients with del(12p13.31) alone or amp(5q31.3) and del(12p13.31) and high Sbeta(2)M had a very poor outcome (5-year overall survival, 20%). This prognostic model was validated in an independent validation cohort of 273 patients with myeloma.ConclusionThese findings demonstrate the power and accessibility of molecular karyotyping to predict outcome in myeloma. In addition, integration of expression of genes residing in the lesions of interest revealed putative features of the disease driving short survival.
| S-EPMC2754906 | biostudies-literature
Project description:BackgroundEsterase enzymes differ in substrate specificity and biological function and may display dysregulated expression in cancer. This study evaluated the biological significance of esterase expression in multiple myeloma (MM).MethodsFor gene expression profiling and evaluation of genomic variants in the Institute for Molecular Medicine Finland (FIMM) cohort, bone marrow aspirates were obtained from patients with newly diagnosed MM (NDMM) or relapsed/refractory MM (RRMM). CD138+ plasma cells were enriched and used for RNA sequencing and analysis, and to evaluate genomic variation. The Multiple Myeloma Research Foundation (MMRF) Relating Clinical Outcomes in MM to Personal Assessment of Genetic Profile (CoMMpass) dataset was used for validation of the findings from FIMM.ResultsMM patients (NDMM, n = 56; RRMM, n = 78) provided 171 bone marrow aspirates (NDMM, n = 56; RRMM, n = 115). Specific esterases exhibited relatively high or low expression in MM, and expression of specific esterases (UCHL5, SIAE, ESD, PAFAH1B3, PNPLA4 and PON1) was significantly altered on progression from NDMM to RRMM. High expression of OVCA2, PAFAH1B3, SIAE and USP4, and low expression of PCED1B, were identified as poor prognostic markers (P < 0.05). The MMRF CoMMpass dataset provided validation that higher expression of PAFAH1B3 and SIAE, and lower expression of PCED1B, were associated with poor prognosis.ConclusionsEsterase gene expression levels change as patients progress from NDMM to RRMM. High expression of OVCA2, PAFAH1B3, USP4 and SIAE, and low expression of PCED1B, are poor prognostic markers in MM, suggesting a role for these esterases in myeloma biology.
| S-EPMC8039029 | biostudies-literature
Project description:PURPOSE:The wide heterogeneity in multiple myeloma (MM) outcome is driven mainly by cytogenetic abnormalities. The current definition of high-risk profile is restrictive and oversimplified. To adapt MM treatment to risk, we need to better define a cytogenetic risk classification. To address this issue, we simultaneously examined the prognostic impact of del(17p); t(4;14); del(1p32); 1q21 gain; and trisomies 3, 5, and 21 in a cohort of newly diagnosed patients with MM. METHODS:Data were obtained from 1,635 patients enrolled in four trials implemented by the Intergroupe Francophone du Myélome. The oldest collection of data were used for model development and internal validation. For external validation, one of the two independent data sets was used to assess the performance of the model in patients treated with more current regimens. Six cytogenetic abnormalities were identified as clinically relevant, and a prognostic index (PI) that was based on the parameter estimates of the multivariable Cox model was computed for all patients. RESULTS:In all data sets, a higher PI was consistently associated with a poor survival outcome. Dependent on the validation cohorts used, hazard ratios for patients in the high-risk category for death were between six and 15 times higher than those of patients in the low-risk category. Among patients with t(4;14) or del(17p), we observed a worse survival in those classified in the high-risk category than in those in the intermediate-risk category. The PI showed good performance for discriminating between patients who died and those who survived (Harrell's concordance index greater than 70%). CONCLUSION:The cytogenetic PI improves the classification of newly diagnosed patients with MM in the high-risk group compared with current classifications. These findings may facilitate the development of risk-adapted treatment strategies.
| S-EPMC6804890 | biostudies-literature
Project description:BackgroundMultiple myeloma (MM) is a disease characterized by heterogeneous clinical presentations as well as complex genetic and molecular abnormalities. In MM, cytogenetic analysis is a challenge because of the low proliferation of malignant plasma cells. Thus, interphase fluorescence in situ hybridization (FISH), performed on sorted plasma cells detected abnormalities independently of a proliferative and infiltrative index. The purpose of this study was to explore, for the first time, the cytogenetic and molecular genetics features in Moroccan patients with multiple myeloma referred exclusively to National Reference Laboratory and to determine their risk stratification based on these features.MethodsWe performed cytogenetic analysis on 93 MM cases, all patients were subjected to FISH analysis, among which 45 patients have benefited from both FISH analysis and standard karyotype.ResultsKaryotype was normal in 78% (35/45) while, it was complex with varied structural and numerical abnormalities in 22% (10/45) of all patients, among which Hyperdiploid karyotype was found in 9% (n = 4 cases) and nonhyperdiploid in 13% (n = 6 cases). The most common numerical abnormalities were gains of chromosomes 3, 5, 9, 15, and 19. Whole chromosome losses were also frequent, affecting chromosomes X, 3, 14, 16 and 22. FISH analysis detected abnormalities in 50% of cases. The translocation t(4;14) and dup (1q) were the most frequent types of anomalies (14% and 13% respectively), followed by (17p) deletion and 14q32/IGH translocations with an undetermined origin (12% each) then the (1p) deletion (4%). For the normal karyotypes, FISH revealed chromosome abnormalities in 46%.ConclusionThis study compares the results of cytogenetic analysis of chromosomal abnormalities in the Moroccan population with other countries. ½ patient showed at least one type of molecular genetic abnormalities. Therefore, the introducing of the cytogenetic analysis is obligatory in the diagnosis of multiple myeloma.
| S-EPMC7507047 | biostudies-literature