Integrated genomic analysis of triple-negative breast cancers reveals novel microRNAs associated with clinical and molecular phenotypes and sheds light on the pathways they control
Autor: | Andrew Tutt, Cheryl Gillett, Brian Burford, David Dornan, Anita Grigoriadis, Pierfrancesco Marra, Sarah E Pinder, Patrycja Gazinska, Lars Holmberg, Grazyna Fedorowicz, Anca Mera, Emanuele de Rinaldis, Zora Modrusan |
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Jazyk: | angličtina |
Předmět: |
Medicin och hälsovetenskap
Pathway analysis DNA Copy Number Variations Transcription Genetic Gene Dosage Genomics Triple Negative Breast Neoplasms Biology Proteomics Medical and Health Sciences Polymorphism Single Nucleotide Transcriptome Breast cancer microRNA Genetics Cluster Analysis Humans Regulation of gene expression Gene Expression Profiling Prognosis Phenotype Gene expression profiling Gene Expression Regulation Neoplastic MicroRNAs miRNAs Cancer research Data integration Female RNA Interference DNA microarray Research Article Follow-Up Studies Signal Transduction Biotechnology |
Zdroj: | BMC Genomics |
ISSN: | 1471-2164 |
DOI: | 10.1186/1471-2164-14-643 |
Popis: | 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 associated with prognosis in the triple-negative tumours and an additional 7 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 influenced by DNA genomic aberrations and to have an overall influence on the expression levels of their predicted targets. Among others, our analyses highlighted the role of miR-17-92 and miR-106b-25, two polycistronic miRNA clusters with known oncogenic functions. We showed that their basal-like subtype specific up-regulation is influenced by increased DNA copy number and contributes to the transcriptional phenotype as well as the activation of oncogenic pathways in basal-like tumours. CONCLUSIONS: This study analyses previously unreported miRNA, mRNA and DNA data and integrates these with pathological and clinical information, from a well-annotated cohort of breast cancers enriched for triple-negative subtypes. It provides a conceptual framework, as well as integrative methods and system-level results and contributes to elucidate the role of miRNAs as biomarkers and modulators of oncogenic processes in these types of tumours. |
Databáze: | OpenAIRE |
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