Project description:Background: This study focuses on the analysis of miRNAs expression data in a cohort of 181 well characterised breast cancer samples composed primarily of triple-negative (ER/PR/HER2-negative) tumours with associated genome-wide DNA and mRNA data, extensive patient follow-up and pathological information. Results: We identified 7 miRNAs with a prognostic role in the triple-negative tumours and an additional 8 prognostic miRNAs when the analysis was extended to the set of all ER-negative cases. miRNAs linked to an unfavourable prognosis were associated with a broad spectrum of motility mechanisms involved in the invasion of stromal tissues, such as cell-adhesion, growth factor-mediated signalling pathways, interaction with the extracellular matrix and cytoskeleton remodelling. When we compared different intrinsic molecular subtypes we found 46 miRNAs that were specifically expressed in one or more intrinsic subtypes. Integrated genomic analyses indicated these miRNAs to be largely influenced by DNA genomic aberrations and to exert a silencing effect on their targets through transcriptional down-regulation. Among others, our analyses highlighted the role of miR17-92 and miR-106b-25, two polycistronic miRNA clusters with known oncogenic functions. We showed that their basal-like specific up-regulation is influenced by increased DNA copy number and contributes to the transcriptional phenotype and the activation of oncogenic pathways in basal-like tumours.Conclusions: This is the first study analysing miRNA, mRNA and DNA data in integration with pathological and clinical information, in a large and well-annotated cohort of triple-negative breast cancers. It provides a conceptual framework, as well as integrative methods and system-level results to elucidate the role of miRNAs as biomarkers and modulators of oncogenic processes in these types of tumours. 181 breast tumour samples were analyzed, extracted from 173 patients. For the great majority of patients (165) only one sample was extracted, while for 8 patients two samples were extracted (biological replicates).

Project description:BACKGROUND:Molecular subtyping of triple-negative breast cancers (TNBCs) via gene expression profiling is essential for understanding the molecular essence of this heterogeneous disease and for guiding individualized treatment. We aim to devise a clinically practical method based on immunohistochemistry (IHC) for the molecular subtyping of TNBCs. MATERIALS AND METHODS:By analyzing the RNA sequencing data on TNBCs from Fudan University Shanghai Cancer Center (FUSCC) (n =?360) and The Cancer Genome Atlas data set (n =?158), we determined markers that can identify specific molecular subtypes. We performed immunohistochemical staining on tumor sections of 210 TNBCs from FUSCC, established an IHC-based classifier, and applied it to another two cohorts (n =?183 and 214). RESULTS:We selected androgen receptor (AR), CD8, FOXC1, and DCLK1 as immunohistochemical markers and classified TNBCs into five subtypes based on the staining results: (a) IHC-based luminal androgen receptor (IHC-LAR; AR-positive [+]), (b) IHC-based immunomodulatory (IHC-IM; AR-negative [-], CD8+), (c) IHC-based basal-like immune-suppressed (IHC-BLIS; AR-, CD8-, FOXC1+), (d) IHC-based mesenchymal (IHC-MES; AR-, CD8-, FOXC1-, DCLK1+), and (e) IHC-based unclassifiable (AR-, CD8-, FOXC1-, DCLK1-). The ? statistic indicated substantial agreement between the IHC-based classification and mRNA-based classification. Multivariate survival analysis suggested that our IHC-based classification was an independent prognostic factor for relapse-free survival. Transcriptomic data and pathological observations implied potential treatment strategies for different subtypes. The IHC-LAR subtype showed relative activation of HER2 pathway. The IHC-IM subtype tended to exhibit an immune-inflamed phenotype characterized by the infiltration of CD8+ T cells into tumor parenchyma. The IHC-BLIS subtype showed high expression of a VEGF signature. The IHC-MES subtype displayed activation of JAK/STAT3 signaling pathway. CONCLUSION:We developed an IHC-based approach to classify TNBCs into molecular subtypes. This IHC-based classification can provide additional information for prognostic evaluation. It allows for subgrouping of TNBC patients in clinical trials and evaluating the efficacy of targeted therapies within certain subtypes. IMPLICATIONS FOR PRACTICE:An immunohistochemistry (IHC)-based classification approach was developed for triple-negative breast cancer (TNBC), which exhibited substantial agreement with the mRNA expression-based classification. This IHC-based classification (a) allows for subgrouping of TNBC patients in large clinical trials and evaluating the efficacy of targeted therapies within certain subtypes, (b) will contribute to the practical application of subtype-specific treatment for patients with TNBC, and (c) can provide additional information beyond traditional prognostic factors in relapse prediction.

Project description:Background: This study focuses on the analysis of miRNAs expression data in a cohort of 181 well characterised breast cancer samples composed primarily of triple-negative (ER/PR/HER2-negative) tumours with associated genome-wide DNA and mRNA data, extensive patient follow-up and pathological information. Results: We identified 7 miRNAs with a prognostic role in the triple-negative tumours and an additional 8 prognostic miRNAs when the analysis was extended to the set of all ER-negative cases. miRNAs linked to an unfavourable prognosis were associated with a broad spectrum of motility mechanisms involved in the invasion of stromal tissues, such as cell-adhesion, growth factor-mediated signalling pathways, interaction with the extracellular matrix and cytoskeleton remodelling. When we compared different intrinsic molecular subtypes we found 46 miRNAs that were specifically expressed in one or more intrinsic subtypes. Integrated genomic analyses indicated these miRNAs to be largely influenced by DNA genomic aberrations and to exert a silencing effect on their targets through transcriptional down-regulation. Among others, our analyses highlighted the role of miR17-92 and miR-106b-25, two polycistronic miRNA clusters with known oncogenic functions. We showed that their basal-like specific up-regulation is influenced by increased DNA copy number and contributes to the transcriptional phenotype and the activation of oncogenic pathways in basal-like tumours.Conclusions: This is the first study analysing miRNA, mRNA and DNA data in integration with pathological and clinical information, in a large and well-annotated cohort of triple-negative breast cancers. It provides a conceptual framework, as well as integrative methods and system-level results to elucidate the role of miRNAs as biomarkers and modulators of oncogenic processes in these types of tumours. 181 breast tumour samples were analyzed, extracted from 173 patients. For the great majority of patients (165) only one sample was extracted, while for 8 patients two samples were extracted (biological replicates).

Project description:BACKGROUND:Abundant evidence shows that triple-negative breast cancer (TNBC) is heterogeneous, and many efforts have been devoted to identifying TNBC subtypes on the basis of genomic profiling. However, few studies have explored the classification of TNBC specifically based on immune signatures that may facilitate the optimal stratification of TNBC patients responsive to immunotherapy. METHODS:Using four publicly available TNBC genomics datasets, we classified TNBC on the basis of the immunogenomic profiling of 29 immune signatures. Unsupervised and supervised machine learning methods were used to perform the classification. RESULTS:We identified three TNBC subtypes that we named Immunity High (Immunity_H), Immunity Medium (Immunity_M), and Immunity Low (Immunity_L) and demonstrated that this classification was reliable and predictable by analyzing multiple different datasets. Immunity_H was characterized by greater immune cell infiltration and anti-tumor immune activities, as well as better survival prognosis compared to the other subtypes. Besides the immune signatures, some cancer-associated pathways were hyperactivated in Immunity_H, including apoptosis, calcium signaling, MAPK signaling, PI3K-Akt signaling, and RAS signaling. In contrast, Immunity_L presented depressed immune signatures and increased activation of cell cycle, Hippo signaling, DNA replication, mismatch repair, cell adhesion molecule binding, spliceosome, adherens junction function, pyrimidine metabolism, glycosylphosphatidylinositol (GPI)-anchor biosynthesis, and RNA polymerase pathways. Furthermore, we identified a gene co-expression subnetwork centered around five transcription factor (TF) genes (CORO1A, STAT4, BCL11B, ZNF831, and EOMES) specifically significant in the Immunity_H subtype and a subnetwork centered around two TF genes (IRF8 and SPI1) characteristic of the Immunity_L subtype. CONCLUSIONS:The identification of TNBC subtypes based on immune signatures has potential clinical implications for TNBC treatment.

Dataset Information

Clinical value of R-spondins in triple-negative and metaplastic breast cancers.

Publications

Clinical value of R-spondins in triple-negative and metaplastic breast cancers.

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