Gene expression profiles of multiple myeloma plasma cell fractions from bone marrow III
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE107843 | GEO | 2018/09/27
REPOSITORIES: GEO
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Project description:Today’s diagnostic tests for multiple myeloma (MM) reflect the criteria of the updated WHO classification based on biomarkers and clinicopathologic heterogeneity. To that end, we propose a new subtyping of myeloma plasma cells (PC) by B-cell subset associated gene signatures (BAGS), from the normal B-cell hierarchy in the bone marrow (BM). To do this, we combined FACS and GEP data from normal BM samples to generate classifiers by BAGS for the PreBI, PreBII, immature (Im), naïve (N), memory (M) and PC subsets. The resultant tumor assignments in available clinical datasets exhibited similar BAGS subtype frequencies in four cohorts across 1302 individual cases. The prognostic impact of BAGS was analyzed in patients treated with high dose melphalan as first line therapy in three prospective trials: UAMS, HOVON65/GMMG-HD4 and MRC Myeloma IX with Affymetrix U133 plus 2.0 microarray data available from diagnostic myeloma PC samples. The BAGS subtypes were significantly associated with progression free (PFS) and overall survival (OS) (PFS, P=3.05e−06 and OS, P=1.06e−11) in a meta-analysis of 926 pts. The major impact was observed within the PreBII and M subtypes conferred with significant inferior prognosis compared to the Im, N and PC subtypes. Cox proportional hazard meta-analysis documented that the BAGS subtypes added significant and independent prognostic information to the TC classification system and ISS staging. BAGS subtype analysis identified transcriptome differences and a number of novel differentially spliced genes. We have identified hierarchal subtype differences in the myeloma plasma cells, with prognostic impact. This observation support an acquired reversible B-cell trait and phenotypic plasticity as a hallmark, also in MM.
2018-09-27 | GSE99635 | GEO
Project description:Today’s diagnostic tests for multiple myeloma (MM) reflect the criteria of the updated WHO classification based on biomarkers and clinicopathologic heterogeneity. To that end, we propose a new subtyping of myeloma plasma cells (PC) by B-cell subset associated gene signatures (BAGS), from the normal B-cell hierarchy in the bone marrow (BM). To do this, we combined FACS and GEP data from normal BM samples to generate classifiers by BAGS for the PreBI, PreBII, immature (Im), naïve (N), memory (M) and PC subsets. The resultant tumor assignments in available clinical datasets exhibited similar BAGS subtype frequencies in four cohorts across 1302 individual cases. The prognostic impact of BAGS was analyzed in patients treated with high dose melphalan as first line therapy in three prospective trials: UAMS, HOVON65/GMMG-HD4 and MRC Myeloma IX with Affymetrix U133 plus 2.0 microarray data available from diagnostic myeloma PC samples. The BAGS subtypes were significantly associated with progression free (PFS) and overall survival (OS) (PFS, P=3.05e−06 and OS, P=1.06e−11) in a meta-analysis of 926 pts. The major impact was observed within the PreBII and M subtypes conferred with significant inferior prognosis compared to the Im, N and PC subtypes. Cox proportional hazard meta-analysis documented that the BAGS subtypes added significant and independent prognostic information to the TC classification system and ISS staging. BAGS subtype analysis identified transcriptome differences and a number of novel differentially spliced genes. We have identified hierarchal subtype differences in the myeloma plasma cells, with prognostic impact. This observation support an acquired reversible B-cell trait and phenotypic plasticity as a hallmark, also in MM.
2018-09-27 | GSE99634 | GEO
Project description:Background: Intrinsic glioma subtypes (IGS) are molecularly similar tumors that can be identified based on unsupervised gene-expression analysis. Here, we have evaluated the clinical relevance of these subtypes within EORTC26951, a randomized phase III clinical trial investigating adjuvant procarbazine, CCNU (lomustine) and vincristine (PCV) chemotherapy in anaplastic oligodendroglial tumors. Our study is the first to include gene-expression profiles of formalin-fixed and paraffin-embedded (FFPE) clinical trial samples. Methods: Gene-expression profiling was performed in 140 samples: 47 fresh frozen and 93 FFPE, on HU133_Plus_2.0 and HuEx_1.0_st arrays (Affymetrix), respectively. Results: All previously identified six intrinsic glioma subtypes are present in EORTC26951. This confirms that different molecular subtypes are present within a well-defined histological subtype. Intrinsic subtypes are highly prognostic for overall- (OS) and progression-free survival (PFS). They are prognostic for PFS independent of clinical (age, performance, tumor location), molecular (1p19qLOH, IDH1 mutation, MGMT methylation) and histological parameters. Combining known molecular (1p19LOH, IDH1) prognostic parameters with intrinsic subtypes improves outcome prediction (Proportion of Explained Variation 30% v 23%). Specific genetic changes (IDH1, 1p19qLOH and EGFR amplification) segregate into different subtypes. We identified one subtype, IGS-9 (characterized by a high percentage of 1p19qLOH and IDH1 mutations), that especially benefits from PCV chemotherapy. Median OS in this subtype was 5.5 years after radiotherapy (RT) alone v 12.8 years after RT/PCV; P=0.0349; HR 2.18, 95% CI [1.06, 4.50]. Conclusion: Intrinsic subtypes are highly prognostic in EORTC26951 and improve outcome prediction when combined with other prognostic factors. Tumors assigned to IGS-9 benefit from adjuvant PCV A total of 140 samples were included in this study, profiles of 95 were FFPE derived samples run on exon arrays. 12 samples (part 2) can also be found in GSE16011 (PMID 19920198 and 16357140), and 6 from Oncomine (part 3).
2013-02-01 | E-GEOD-43107 | biostudies-arrayexpress
Project description:Background: Intrinsic glioma subtypes (IGS) are molecularly similar tumors that can be identified based on unsupervised gene-expression analysis. Here, we have evaluated the clinical relevance of these subtypes within EORTC26951, a randomized phase III clinical trial investigating adjuvant procarbazine, CCNU (lomustine) and vincristine (PCV) chemotherapy in anaplastic oligodendroglial tumors. Our study is the first to include gene-expression profiles of formalin-fixed and paraffin-embedded (FFPE) clinical trial samples. Methods: Gene-expression profiling was performed in 140 samples: 47 fresh frozen and 93 FFPE, on HU133_Plus_2.0 and HuEx_1.0_st arrays (Affymetrix), respectively. Results: All previously identified six intrinsic glioma subtypes are present in EORTC26951. This confirms that different molecular subtypes are present within a well-defined histological subtype. Intrinsic subtypes are highly prognostic for overall- (OS) and progression-free survival (PFS). They are prognostic for PFS independent of clinical (age, performance, tumor location), molecular (1p19qLOH, IDH1 mutation, MGMT methylation) and histological parameters. Combining known molecular (1p19LOH, IDH1) prognostic parameters with intrinsic subtypes improves outcome prediction (Proportion of Explained Variation 30% v 23%). Specific genetic changes (IDH1, 1p19qLOH and EGFR amplification) segregate into different subtypes. We identified one subtype, IGS-9 (characterized by a high percentage of 1p19qLOH and IDH1 mutations), that especially benefits from PCV chemotherapy. Median OS in this subtype was 5.5 years after radiotherapy (RT) alone v 12.8 years after RT/PCV; P=0.0349; HR 2.18, 95% CI [1.06, 4.50]. Conclusion: Intrinsic subtypes are highly prognostic in EORTC26951 and improve outcome prediction when combined with other prognostic factors. Tumors assigned to IGS-9 benefit from adjuvant PCV A total of 140 samples were included in this study, profiles of 95 were FFPE derived samples run on exon arrays. 12 samples (part 2) can also be found in GSE16011 (PMID 19920198 and 16357140), and 6 from Oncomine (part 3).
2013-02-01 | E-GEOD-43353 | biostudies-arrayexpress
Project description:Background: Intrinsic glioma subtypes (IGS) are molecularly similar tumors that can be identified based on unsupervised gene-expression analysis. Here, we have evaluated the clinical relevance of these subtypes within EORTC26951, a randomized phase III clinical trial investigating adjuvant procarbazine, CCNU (lomustine) and vincristine (PCV) chemotherapy in anaplastic oligodendroglial tumors. Our study is the first to include gene-expression profiles of formalin-fixed and paraffin-embedded (FFPE) clinical trial samples. Methods: Gene-expression profiling was performed in 140 samples: 47 fresh frozen and 93 FFPE, on HU133_Plus_2.0 and HuEx_1.0_st arrays (Affymetrix), respectively. Results: All previously identified six intrinsic glioma subtypes are present in EORTC26951. This confirms that different molecular subtypes are present within a well-defined histological subtype. Intrinsic subtypes are highly prognostic for overall- (OS) and progression-free survival (PFS). They are prognostic for PFS independent of clinical (age, performance, tumor location), molecular (1p19qLOH, IDH1 mutation, MGMT methylation) and histological parameters. Combining known molecular (1p19LOH, IDH1) prognostic parameters with intrinsic subtypes improves outcome prediction (Proportion of Explained Variation 30% v 23%). Specific genetic changes (IDH1, 1p19qLOH and EGFR amplification) segregate into different subtypes. We identified one subtype, IGS-9 (characterized by a high percentage of 1p19qLOH and IDH1 mutations), that especially benefits from PCV chemotherapy. Median OS in this subtype was 5.5 years after radiotherapy (RT) alone v 12.8 years after RT/PCV; P=0.0349; HR 2.18, 95% CI [1.06, 4.50]. Conclusion: Intrinsic subtypes are highly prognostic in EORTC26951 and improve outcome prediction when combined with other prognostic factors. Tumors assigned to IGS-9 benefit from adjuvant PCV A total of 140 samples were included in this study, profiles of 95 were FFPE derived samples run on exon arrays. 12 samples (part 2) can also be found in GSE16011 (PMID 19920198 and 16357140), and 6 from Oncomine (part 3).
2013-02-01 | E-GEOD-43115 | biostudies-arrayexpress
Project description:Background: Intrinsic glioma subtypes (IGS) are molecularly similar tumors that can be identified based on unsupervised gene-expression analysis. Here, we have evaluated the clinical relevance of these subtypes within EORTC26951, a randomized phase III clinical trial investigating adjuvant procarbazine, CCNU (lomustine) and vincristine (PCV) chemotherapy in anaplastic oligodendroglial tumors. Our study is the first to include gene-expression profiles of formalin-fixed and paraffin-embedded (FFPE) clinical trial samples. Methods: Gene-expression profiling was performed in 140 samples: 47 fresh frozen and 93 FFPE, on HU133_Plus_2.0 and HuEx_1.0_st arrays (Affymetrix), respectively. Results: All previously identified six intrinsic glioma subtypes are present in EORTC26951. This confirms that different molecular subtypes are present within a well-defined histological subtype. Intrinsic subtypes are highly prognostic for overall- (OS) and progression-free survival (PFS). They are prognostic for PFS independent of clinical (age, performance, tumor location), molecular (1p19qLOH, IDH1 mutation, MGMT methylation) and histological parameters. Combining known molecular (1p19LOH, IDH1) prognostic parameters with intrinsic subtypes improves outcome prediction (Proportion of Explained Variation 30% v 23%). Specific genetic changes (IDH1, 1p19qLOH and EGFR amplification) segregate into different subtypes. We identified one subtype, IGS-9 (characterized by a high percentage of 1p19qLOH and IDH1 mutations), that especially benefits from PCV chemotherapy. Median OS in this subtype was 5.5 years after radiotherapy (RT) alone v 12.8 years after RT/PCV; P=0.0349; HR 2.18, 95% CI [1.06, 4.50]. Conclusion: Intrinsic subtypes are highly prognostic in EORTC26951 and improve outcome prediction when combined with other prognostic factors. Tumors assigned to IGS-9 benefit from adjuvant PCV A total of 140 samples were included in this study, profiles of 95 were FFPE derived samples run on exon arrays. 12 samples (part 2) can also be found in GSE16011 (PMID 19920198 and 16357140), and 6 from Oncomine (part 3).
2013-02-01 | E-GEOD-43114 | biostudies-arrayexpress
Project description:Background: Intrinsic glioma subtypes (IGS) are molecularly similar tumors that can be identified based on unsupervised gene-expression analysis. Here, we have evaluated the clinical relevance of these subtypes within EORTC26951, a randomized phase III clinical trial investigating adjuvant procarbazine, CCNU (lomustine) and vincristine (PCV) chemotherapy in anaplastic oligodendroglial tumors. Our study is the first to include gene-expression profiles of formalin-fixed and paraffin-embedded (FFPE) clinical trial samples. Methods: Gene-expression profiling was performed in 140 samples: 47 fresh frozen and 93 FFPE, on HU133_Plus_2.0 and HuEx_1.0_st arrays (Affymetrix), respectively. Results: All previously identified six intrinsic glioma subtypes are present in EORTC26951. This confirms that different molecular subtypes are present within a well-defined histological subtype. Intrinsic subtypes are highly prognostic for overall- (OS) and progression-free survival (PFS). They are prognostic for PFS independent of clinical (age, performance, tumor location), molecular (1p19qLOH, IDH1 mutation, MGMT methylation) and histological parameters. Combining known molecular (1p19LOH, IDH1) prognostic parameters with intrinsic subtypes improves outcome prediction (Proportion of Explained Variation 30% v 23%). Specific genetic changes (IDH1, 1p19qLOH and EGFR amplification) segregate into different subtypes. We identified one subtype, IGS-9 (characterized by a high percentage of 1p19qLOH and IDH1 mutations), that especially benefits from PCV chemotherapy. Median OS in this subtype was 5.5 years after radiotherapy (RT) alone v 12.8 years after RT/PCV; P=0.0349; HR 2.18, 95% CI [1.06, 4.50]. Conclusion: Intrinsic subtypes are highly prognostic in EORTC26951 and improve outcome prediction when combined with other prognostic factors. Tumors assigned to IGS-9 benefit from adjuvant PCV A total of 140 samples were included in this study, profiles of 95 were FFPE derived samples run on exon arrays. 12 samples (part 2) can also be found in GSE16011 (PMID 19920198 and 16357140), and 6 from Oncomine (part 3).
2013-02-01 | E-GEOD-43113 | biostudies-arrayexpress
Project description:Background: Intrinsic glioma subtypes (IGS) are molecularly similar tumors that can be identified based on unsupervised gene-expression analysis. Here, we have evaluated the clinical relevance of these subtypes within EORTC26951, a randomized phase III clinical trial investigating adjuvant procarbazine, CCNU (lomustine) and vincristine (PCV) chemotherapy in anaplastic oligodendroglial tumors. Our study is the first to include gene-expression profiles of formalin-fixed and paraffin-embedded (FFPE) clinical trial samples. Methods: Gene-expression profiling was performed in 140 samples: 47 fresh frozen and 93 FFPE, on HU133_Plus_2.0 and HuEx_1.0_st arrays (Affymetrix), respectively. Results: All previously identified six intrinsic glioma subtypes are present in EORTC26951. This confirms that different molecular subtypes are present within a well-defined histological subtype. Intrinsic subtypes are highly prognostic for overall- (OS) and progression-free survival (PFS). They are prognostic for PFS independent of clinical (age, performance, tumor location), molecular (1p19qLOH, IDH1 mutation, MGMT methylation) and histological parameters. Combining known molecular (1p19LOH, IDH1) prognostic parameters with intrinsic subtypes improves outcome prediction (Proportion of Explained Variation 30% v 23%). Specific genetic changes (IDH1, 1p19qLOH and EGFR amplification) segregate into different subtypes. We identified one subtype, IGS-9 (characterized by a high percentage of 1p19qLOH and IDH1 mutations), that especially benefits from PCV chemotherapy. Median OS in this subtype was 5.5 years after radiotherapy (RT) alone v 12.8 years after RT/PCV; P=0.0349; HR 2.18, 95% CI [1.06, 4.50]. Conclusion: Intrinsic subtypes are highly prognostic in EORTC26951 and improve outcome prediction when combined with other prognostic factors. Tumors assigned to IGS-9 benefit from adjuvant PCV A total of 140 samples were included in this study, profiles of 95 were FFPE derived samples run on exon arrays. 12 samples (part 2) can also be found in GSE16011 (PMID 19920198 and 16357140), and 6 from Oncomine (part 3).
2013-02-01 | E-GEOD-43116 | biostudies-arrayexpress
Project description:The AVAglio and RTOG-0825 randomized, placebo-controlled phase III trials in newly diagnosed glioblastoma reported prolonged progression-free survival (PFS), but not overall survival (OS), with the addition of bevacizumab to radiotherapy/temozolomide. To establish whether certain patient subgroups derived OS benefit from the addition of bevacizumab to first-line standard-of-care therapy, AVAglio patients were retrospectively evaluated for molecular subtype, and bevacizumab efficacy assessed for each patient subgroup. A multivariate analysis accounting for prognostic covariates revealed that bevacizumab conferred a significant OS advantage versus placebo for patients with Proneural IDH1 wild-type tumors (17.1 v 12.8 months, respectively; hazard ratio, 0.43; 95% CI, 0.26 to 0.73; P = .002). This analysis also revealed an interaction between the Proneural subtype biomarker and treatment arm (P = .023). The group of patients with Mesenchymal and Proneural tumors derived a PFS benefit from bevacizumab, compared with placebo; however, this translated to an OS benefit in the Proneural subset only. Retrospective analysis of AVAglio data suggests that patients with IDH1 wild-type Proneural glioblastoma may derive OS benefit from first-line bevacizumab treatment. The predictive value of the Proneural subtype observed in AVAglio should be validated in an independent dataset. A total of 349 (bevacizumab arm, n = 171; placebo arm, n = 178) pretreatment specimens from AVAglio patients (total n = 921) were available for biomarker analysis. Samples were profiled for gene expression and isocitrate dehydrogenase 1 (IDH1) mutation status and classified into previously identified molecular subtypes. PFS and OS were assessed within each subtype.
2016-07-06 | E-GEOD-84010 | biostudies-arrayexpress
Project description:Purpose Current diagnostic tests for diffuse large B-cell lymphoma use the updated WHO criteria based on biologic, morphologic, and clinical heterogeneity. We propose a refined classification sys-tem based on subset-specific B-cell–associated gene signatures (BAGS) in the normal B-cell hierarchy, hypothesizing that it can provide new biologic insight and diagnostic and prognostic value. Patients and Methods We combined fluorescence-activated cell sorting, gene expression profiling, and statistical modeling to generate BAGS for naive, centrocyte, centroblast, memory, and plasmablast B cells from normal human tonsils. The impact of BAGS-assigned subtyping was analyzed using five clinical cohorts (treated with cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP], n _ 270; treated with rituximab plus CHOP [R-CHOP], n _ 869) gathered across geo-graphic regions, time eras, and sampling methods. The analysis estimated subtype frequencies and drug-specific resistance and included a prognostic meta-analysis of patients treated with first-line R-CHOP therapy. Results Similar BAGS subtype frequencies were assigned across 1,139 samples from five different co-horts. Among R-CHOP–treated patients, BAGS assignment was significantly associated with overall survival and progression-free survival within the germinal center B-cell–like subclass; the centrocyte subtype had a superior prognosis compared with the centroblast subtype. In agreement with the observed therapeutic outcome, centrocyte subtypes were estimated as being less resistant than the centroblast subtype to doxorubicin and vincristine. The centroblast subtype had a complex genotype, whereas the centrocyte subtype had high TP53 mutation and insertion/deletion frequencies and expressed LMO2, CD58, and stromal-1–signature and major histocompatibility complex class II–signature genes, which are known to have a positive impact on prognosis. Conclusion Further development of a diagnostic platform using BAGS-assigned subtypes may allow pathogenetic studies to improve disease management.
2015-03-24 | GSE56313 | GEO