Analytical validation of SKY92 for the identification of high-risk Multiple Myeloma
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PROVIDER: PRJNA668314 | ENA |
REPOSITORIES: ENA
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Project description:Multiple myeloma is an incurable plasma cell cancer with a large variability in survival. Multiple myeloma patients classified high risk by the SKY92 gene expression classifier are at high risk of relapse and short survival. We performed analytical validation of the SKY92 assay with primary bone marrow specimens from 12 multiple myeloma patients and 7 reference cell line specimens. The SKY92 results were 100% concordant - with the reference and/or their expected result - for sensitivity, specificity, microarray stability and RLT buffer stability; The SKY92 results were 90% concordant for primary specimen stability, 96.4% for intermediate precision and 80%-100% for RNA stability. For the cell-line reproducibility the concordance was at least 92.9%, except for one near-cut point specimen. For the clinical specimen reproducibility, the concordance was 100%, except for two near-cut point specimens. Three independent laboratories were concordant in ≥ 77.8% and ≥ 92.9% of experiments (respectively patient specimens and cell lines). Statistical acceptance thresholds were developed as Delta ≤ 1.48 (change in SKY92 score) and standard deviation ≤ 0.45 (SD across SKY92 scores). Using the CLSI method of choice (EP05-A2/A3), restricted maximum likelihood or REML, the observed Deltas (0 - 1.14) and standard deviations (0.22-0.31) passed acceptance criteria. The analytical validation for the SKY92 assay as a prognostic molecular test for individual multiple myeloma patients is therefore successfully proven.
2020-10-28 | GSE159289 | GEO
Project description:We recently defined a gene expression-based signature of high-risk multiple myeloma; this predictive signature was developed with and independently validated for newly diagnosed patients treated with high dose therapy and stem cell rescue. Here we use Phase 3 clinical trial data to show that this signature also predicts short survival in relapsed disease treated with single agent bortezomib or high dose dexamethasone. In addition, a survival signature derived with relapsed myeloma samples identified newly diagnosed patients with short survival. Taken together these data suggest that a similar biology underlies poor outcome in both newly diagnosed and relapsed myeloma and provide strong evidence that the high-risk signature is a powerful tool to identify patients who are candidates for new therapeutic regimens. Keywords: Model validation See above (Series_summary)
2011-08-19 | E-GEOD-8991 | biostudies-arrayexpress
Project description:We recently defined a gene expression-based signature of high-risk multiple myeloma; this predictive signature was developed with and independently validated for newly diagnosed patients treated with high dose therapy and stem cell rescue. Here we use Phase 3 clinical trial data to show that this signature also predicts short survival in relapsed disease treated with single agent bortezomib or high dose dexamethasone. In addition, a survival signature derived with relapsed myeloma samples identified newly diagnosed patients with short survival. Taken together these data suggest that a similar biology underlies poor outcome in both newly diagnosed and relapsed myeloma and provide strong evidence that the high-risk signature is a powerful tool to identify patients who are candidates for new therapeutic regimens. Keywords: Model validation
2011-08-20 | GSE8991 | GEO
Project description:Multiple myeloma is a plasma cell malignancy of the bone marrow. Despite therapeutic advances, multiple myeloma remains incurable and better risk stratification as well as new therapies are therefore highly needed. The proteome of multiple myeloma has not been systematically assessed before and holds the potential to uncover additional insight into disease biology and improved prognostic models. Here, we provide a comprehensive multi-omics analysis including deep tandem mass tags (TMT)-based quantitative global (phospho)proteomics, RNA sequencing and nanopore DNA sequencing of 138 primary patient-derived plasma cell malignancies encompassing treatment-naive multiple myeloma patients treated in clinical trials, plasma cell leukemia, and the premalignancy monoclonal gammopathy of undetermined significance (MGUS), as well as healthy controls. We found that the (phospho)proteome of malignant plasma cells is highly deregulated as compared to healthy plasma cells and is both defined by chromosomal alterations and extensive post-transcriptional regulation. A protein signature was identified that is associated with aggressive disease and more predictive for outcome than cytogenetic-based risk assessment in newly diagnosed multiple myeloma. Integration with functional genetics and single-cell sequencing revealed generally and genetic subtype-specific deregulated proteins and pathways in plasma cell malignancies that include novel potential targets for (immuno)therapies. These findings provide new insights in the biology of multiple myeloma and will be a unique resource for investigating new therapeutic approaches.
2024-07-09 | PXD038437 | Pride
Project description:Multiple myeloma is a plasma cell malignancy of the bone marrow. Despite therapeutic advances, multiple myeloma remains incurable and better risk stratification as well as new therapies are therefore highly needed. The proteome of multiple myeloma has not been systematically assessed before and holds the potential to uncover additional insight into disease biology and improved prognostic models. Here, we provide a comprehensive multi-omics analysis including deep tandem mass tag (TMT)-based quantitative global (phospho)proteomics, RNA sequencing and nanopore DNA sequencing of 138 primary patient-derived plasma cell malignancies encompassing treatment-naive multiple myeloma patients treated in clinical trials, plasma cell leukemia, and the premalignancy monoclonal gammopathy of undetermined significance (MGUS), as well as healthy controls. We found that the (phospho)proteome of malignant plasma cells is highly deregulated as compared to healthy plasma cells and is both defined by chromosomal alterations and extensive post-transcriptional regulation. A protein signature was identified that is associated with aggressive disease and more predictive for outcome than cytogenetic-based risk assessment in newly diagnosed multiple myeloma. Integration with functional genetics and single-cell sequencing revealed generally and genetic subtype-specific deregulated proteins and pathways in plasma cell malignancies that include novel potential targets for (immuno)therapies. These findings provide new insights in the biology of multiple myeloma and will be a unique resource for investigating new therapeutic approaches.
2024-07-09 | PXD043580 | Pride
Project description:Purpose Survival of patients with multiple myeloma is highly heterogeneous from periods of few weeks to more than ten years. We used gene-expression profiles of myeloma cells obtained at diagnosis to identify broadly applicable prognostic markers. Methods In a training set of 182 patients, we used supervised methods to identify individual genes associated with length of survival. A survival model was built from these genes. The validity of our model was assessed in our test set of 68 patients and in three independent cohorts comprising 853 multiple myeloma patients. Results The 15 strongest genes associated with the length of survival were used to calculate a risk score and to stratify patients in low-risk and high-risk. The survival-predictor score was significantly associated with survival in both the training and test sets and in the external validation cohorts. The Kaplan Meier estimates of rates of survival at 3 years were 90.5 percent (95 percent CI, 85.6 – 95.3), and 47.4 (95 percent CI, 33.5 - 60.1) respectively in our patients having a low-risk or high-risk, independently of traditional prognostic factors. High-risk patients constituted a homogeneous biological entity characterized by the overexpression of genes involved in cell cycle progression and its surveillance, while low-risk patients were heterogeneous and displayed hyperdiploid signatures. Conclusion Gene expression-based survival prediction and molecular features associated with high-risk patients may be useful for developing prognostic markers and may provide basis to treat these patients with new targeted anti-mitotics. Keywords: Gene-expression profiling
2008-08-05 | GSE7039 | GEO
Project description:<h4><strong>BACKGROUND:</strong> Multiple myeloma is characterized by clonal proliferation of malignant plasma cells in the bone marrow that produce monoclonal immunoglobulins. N-glycosylation changes of these monoclonal immunoglobulins have been reported in multiple myeloma, but previous studies only detected limited serum N-glycan features.</h4><h4><strong>METHODS:</strong> Here, a more detailed study of the human serum N-glycome of 91 multiple myeloma patients and 51 controls was performed. We additionally analyzed sequential samples from patients (n = 7) which were obtained at different time points during disease development as well as 16 paired blood serum and bone marrow plasma samples. N-glycans were enzymatically released and measured by mass spectrometry after linkage specific derivatization of sialic acids.</h4><h4><strong>RESULTS:</strong> A decrease in both α2,3- and α2,6-sialylation, galactosylation and an increase in fucosylation within complex-type N-glycans were found in multiple myeloma patients compared to controls, as well as a decrease in difucosylation of diantennary glycans. The observed glycosylation changes were present in all ISS stages, including the 'low-risk' ISS I. In individual patients, difucosylation of diantennary glycans decreased with development of the disease. Protein N-glycosylation features from blood and bone marrow showed strong correlation. Moreover, associations of monoclonal immunoglobulin (M-protein) and albumin levels with glycan traits were discovered in multiple myeloma patients.</h4><h4><strong>CONCLUSIONS & GENERAL SIGNIFICANCE: </strong>In conclusion, serum protein N-glycosylation analysis could successfully distinguish multiple myeloma from healthy controls. Further studies are needed to assess the potential roles of glycan trait changes and the associations of glycans with clinical parameters in multiple myeloma early detection and prognosis.</h4>
2022-04-27 | MTBLS676 | MetaboLights
Project description:Performing GWAS on multiple myeloma in relation to the development of the toxicity neuropathy. This set was used as validation set. We performed a genome-wide association study using Affymetrix HD-SNP arrays 6.0 to identify risk variants for developing bortezomib-induced peripheral neuropathy (BiPN) in 469 multiple myeloma (MM) patients who received bortezomib-dexamethasone therapy prior to autologous stem-cell transplantation and conducted validation in an independent cohort of 116 MM patients. We identified one previously unreported BiPN risk locus at 21q22.3 (rs2839629, PKNOX1; OR = 0.53, 95% CI: [0.40-0.69]). PKNOX1 is known to regulate MCP-1, a potent mediator of chemotherapy-induced peripheral neuropathy. rs2839629 is in strong linkage disequilibrium ( r2 = 0.87) with rs915854, localized 6.5kb centromeric to CBS encoding endogenous H2S-producing enzyme. CBS-H2S signalling pathway is implicated in the pathogenesis of a variety of neurodegenerative and inflammatory disorders, and specifically in neuropathy models. Our data provide conclusive evidence for genetic susceptibility to BiPN in MM and new potential targets in neuro-protective strategies of treatment.
2016-06-01 | GSE66903 | GEO