Subtype-dependent prognostic relevance of an interferon-induced pathway metagene in human node negative breast cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE37181 | GEO | 2014/05/01
SECONDARY ACCESSION(S): PRJNA158617
REPOSITORIES: GEO
Similar Datasets
Project description:We identified and validated the pivotal role for a metagene containing IFN-induced genes in association to higher metastatic potential as a function of the specific molecular subtype Fresh frozen primary tumors were collected at the time of diagnosis from 123 patients with operable breast cancer previously untreated and undergoing radical or conservative surgery at the Istituto Nazionale Tumori of Milano (INTM) between1990 and 1998. All patients were pathologically defined as axillary node negative and were not submitted to any type of adjuvant systemic treatment until relapse. Patients were selected in order to have a comparable pattern of classical risk factors (age, tumor size).
2014-05-01 | E-GEOD-37181 | biostudies-arrayexpress
Project description:The majority of gene expression signatures developed to predict the likelihood to relapse in breast cancer (BC) patients assigns a high risk score to patients with Estrogen Receptor (ER) negative or highly proliferating tumors. We aimed to identify a signature of differentially expressed (DE) metagenes, rather than single DE genes, associated with distant metastases beyond classical risk factors. We used 105 gene expression profiles from consecutive BCs to identify metagenes whose prognostic role was defined on an independent series of 92 ESR1+/ERBB2- node-negative BCs (42 cases developing metastases within 5 years from diagnosis and 50 cases metastasis-free for more than 5 years, comparable for age, tumor size, ER status and surgery). Findings were validated on publicly available datasets of 684 node-negative BCs including all the subtypes. Only a metagene containing interferon-induced genes (IFN metagene) proved to be predictive of distant metastasis in our series of patients with ESR1+/ERBB2- tumors (P = 0.029), and such a finding was validated on 457 ESR1+/ERBB2- BCs from public datasets (P = 0.0424). Conversely, the IFN metagene was associated with a low risk of metastasis in 104 ERBB2+ tumors (P = 0.0099) whereas it did not prove to significantly affect prognosis in 123 ESR1-/ERBB2- tumors (P = 0.2235). A complex prognostic interaction was revealed in ESR1+/ERBB2- and ERBB2+ tumors when the association between the IFN metagene and a T-cell metagene was considered. The study confirms the importance of analyzing prognostic variables separately within BC subtypes, highlights the advantages of using metagenes rather than genes, and finally identifies in node-negative ESR1+/ERBB2- BCs, the unfavorable role of high IFN metagene expression.
| S-EPMC5528564 | biostudies-literature
Project description:We identified and validated the pivotal role for a metagene containing IFN-induced genes in association to higher metastatic potential as a function of the specific molecular subtype Fresh frozen primary tumors were collected at the time of diagnosis from 123 patients with operable breast cancer previously untreated and undergoing radical or conservative surgery at the Istituto Nazionale Tumori of Milano (INTM) between1990 and 1998. All patients were pathologically defined as axillary node negative and were not submitted to any type of adjuvant systemic treatment until relapse. Patients were selected in order to have a comparable pattern of classical risk factors (age, tumor size).
| S-ECPF-GEOD-37181 | biostudies-other
Project description:Estrogen receptor (ER) expression and proliferative activity are established prognostic factors in breast cancer. In a search for additional prognostic motives we analyzed the gene expression patterns of 200 tumors of patients who were not treated by systemic therapy after surgery using a discovery approach. After performing hierarchical cluster analysis, we identified co-regulated genes related to the biological process of proliferation, steroid hormone receptor expression, as well as B cell and T cell infiltration. We calculated metagenes as surrogate for all genes contained within a particular cluster and visualized the relative expression in relation to time to metastasis with principal component analysis. Distinct patterns led to the hypothesis of a prognostic role of the immune system in tumors with high expression of proliferation associated genes. In multivariate Cox regression analysis the proliferation metagene showed a significant association with metastasis-free survival of the whole discovery cohort (Hazard Ratio (HR) 2.20, 95% confidence interval (CI) 1.40-3.46). The B cell metagene showed additional independent prognostic information in carcinomas with high proliferative activity (HR 0.66, 95% CI 0.46 - 0.97). A prognostic influence of the B-cell metagene was independently confirmed by multivariate analysis in a first validation cohort enriched for high grade tumors (n=286, HR 0.78, 95% CI 0.62-0.98), and a second validation cohort enriched for younger patients (n=302, HR 0.83, 95% CI 0.7-0.97). Thus, we could demonstrate in three cohorts of untreated node-negative breast cancer patients, that the humoral immune system plays a pivotal role for metastasis-free survival of carcinomas of the breast. Keywords: disease state analysis
2008-07-01 | GSE11121 | GEO
Project description:Estrogen receptor (ER) expression and proliferative activity are established prognostic factors in breast cancer. In a search for additional prognostic motives we analyzed the gene expression patterns of 200 tumors of patients who were not treated by systemic therapy after surgery using a discovery approach. After performing hierarchical cluster analysis, we identified co-regulated genes related to the biological process of proliferation, steroid hormone receptor expression, as well as B cell and T cell infiltration. We calculated metagenes as surrogate for all genes contained within a particular cluster and visualized the relative expression in relation to time to metastasis with principal component analysis. Distinct patterns led to the hypothesis of a prognostic role of the immune system in tumors with high expression of proliferation associated genes. In multivariate Cox regression analysis the proliferation metagene showed a significant association with metastasis-free survival of the whole discovery cohort (Hazard Ratio (HR) 2.20, 95% confidence interval (CI) 1.40-3.46). The B cell metagene showed additional independent prognostic information in carcinomas with high proliferative activity (HR 0.66, 95% CI 0.46 - 0.97). A prognostic influence of the B-cell metagene was independently confirmed by multivariate analysis in a first validation cohort enriched for high grade tumors (n=286, HR 0.78, 95% CI 0.62-0.98), and a second validation cohort enriched for younger patients (n=302, HR 0.83, 95% CI 0.7-0.97). Thus, we could demonstrate in three cohorts of untreated node-negative breast cancer patients, that the humoral immune system plays a pivotal role for metastasis-free survival of carcinomas of the breast. Experiment Overall Design: Population based N0 untreated breast cancer cohort study including 200 samples
2008-10-21 | E-GEOD-11121 | biostudies-arrayexpress
Project description:Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype and the lack of specific signature makes difficult the development of targeted therapeutic strategy. We previously found that PRICKLE1, an evolutionary conserved protein acting as a regulator of vertebrate development, is upregulated in TNBC. Proteomic approaches allowed us to decipher the protein complex associated to PRICKLE1 in TNBC. Within that complex, we identified a large subset of proteins involved in the regulation of Rho-GTPase family members. We build a metagene with regulators of small G-protein activity and we found that this metagene is overexpressed in TNBC and is a poor prognosis marker. We analyzed the combination of the metagene expression and PRICKLE1 expression and identified that combined expression of ECT2 and PRICKLE1 provides a worst prognosis than PRICKLE1 expression alone in TNBC. ECT2 is a GEF for Rac1 and we showed that PRICKLE1 regulate the enzymatic activity of ECT2. Finally, we also observed that Ect2 and Prickle1 are functionally connected during evolution since both act synergistically to coordinate cellular movement during vertebrate gastrulation. Our results demonstrate the pivotal role of PRICKLE1 in TNBC and build the path for development of targeted therapeutic strategies to heal TNBC patients.
2019-10-15 | PXD011253 | Pride
Project description:Interferons are crucial for adaptive immunity and play an important role in the immune landscape of breast cancer. Using microarray-based gene expression analysis, we examined the subtype specific prognostic significance of interferon-γ (IFN-γ) as a single gene as well as an IFN-γ signature covering the signaling pathway in 461 breast cancer patients. Prognostic significance of IFN-γ as well as the IFN-γ signature for metastasis-free survival (MFS) were examined using Kaplan Meier as well as univariate and multivariate Cox regression analyses in the whole cohort and in different molecular subtypes. Kaplan Meier curves and univariate Cox regression analyses showed that the prognostic significance of IFN-γ as a single gene was limited to basal-like breast cancer (P=0.033). In contrast, the IFN-γ associated gene signature was a significant prognostic factor in the whole cohort (HR 1.554; 95%CI 1.1099-2.199; P=0.013) as well as in the luminal B (P=0.007) and HER2-positive (P=0.033) molecular subtype with borderline significance in basal-like breast cancer(P=0.050). In multivariate analysis, the IFN-γ signature retained its independent prognostic significance (HR 2.287; 95% CI: 1.410-3.633;P<0.001) in the entire cohort. These results underline the subtype-dependent prognostic influence of the immune system in early breast cancer.
2020-09-22 | GSE158309 | GEO
Project description:Type I interferons (IFN-I) exert pleiotropic biological effects during viral infections, balancing virus control versus immune-mediated pathologies and have been successfully employed for the treatment of viral diseases. Humans express twelve IFN-alpha (α) subtypes, which activate downstream signalling cascades and result in distinct patterns of immune responses and differential antiviral responses. Inborn errors in type I IFN immunity and the presence of anti- IFN autoantibodies account for very severe courses of COVID-19, therefore, early administration of type I IFNs may be protective against life-threatening disease. Here we comprehensively analysed the antiviral activity of all IFNα subtypes against SARS-CoV-2 to identify the underlying immune signatures and explore their therapeutic potential. Prophylaxis of primary human airway epithelial cells (hAEC) with different IFNα subtypes during SARS-CoV-2 infection uncovered distinct functional classes with high, intermediate and low antiviral IFNs. In particular IFNα5 showed superior antiviral activity against SARS-CoV-2 infection. Dose-dependency studies further displayed additive effects upon co-administered with the broad antiviral drug remdesivir in cell culture. Transcriptomics of IFN-treated hAEC revealed different transcriptional signatures, uncovering distinct, intersecting and prototypical genes of individual IFNα subtypes. Global proteomic analyses systematically assessed the abundance of specific antiviral key effector molecules which are involved in type I IFN signalling pathways, negative regulation of viral processes and immune effector processes for the potent antiviral IFNα5. Taken together, our data provide a systemic, multi-modular definition of antiviral host responses mediated by defined type I IFNs. This knowledge shall support the development of novel therapeutic approaches against SARS-CoV-2.
2022-02-09 | PXD026079 | Pride
Project description:We analyzed gene expression profile in node negative breast tumor for molecular subtype classification
2018-02-16 | GSE104549 | GEO