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Identifying the driver miRNAs with somatic copy number alterations driving dysregulated ceRNA networks in cancers
Renjie Dou1, Shaobo Kang1, Huan Yang1
1College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, Heilongjiang, China.
Background:
MicroRNAs (miRNAs) play critical roles in cancer initiation and progression, which were critical components to maintain the dynamic balance of competing endogenous RNA (ceRNA) networks. Somatic copy number alterations (SCNAs) in the cancer genome could disturb the transcriptome level of miRNA to deregulate this balance. However, the driving effects of SCNAs of miRNAs were insufficiently understood.
Methods:
In this study, we proposed a method to dissect the functional roles of miRNAs under different copy number states and identify driver miRNAs by integrating miRNA SCNAs profile, miRNA-target relationships and expression profiles of miRNA, mRNA and lncRNA.
Results:
Applying our method to 813 TCGA breast cancer (BRCA) samples, we identified 29 driver miRNAs whose SCNAs significantly and concordantly regulated their own expression levels and further inversely dysregulated expression levels of their targets or disturbed the miRNA-target networks they directly involved. Based on miRNA-target networks, we further constructed dynamic ceRNA networks driven by driver SCNAs of miRNAs and identified three different patterns of SCNA interference in the miRNA-mediated dynamic ceRNA networks. Survival analysis of driver miRNAs showed that high-level amplifications of four driver miRNAs (including has-miR-30d-3p, has-mir-30b-5p, has-miR-30d-5p and has-miR-151a-3p) in 8q24 characterized a new BRCA subtype with poor prognosis and contributed to the dysfunction of cancer-associated hallmarks in a complementary way. The SCNAs of driver miRNAs across different cancer types contributed to the cancer development by dysregulating different components of the same cancer hallmarks, suggesting the cancer specificity of driver miRNA.
Conclusions:
These results demonstrate the efficacy of our method in identifying driver miRNAs and elucidating their functional roles driven by endogenous SCNAs, which is useful for interpreting cancer genomes and pathogenic mechanisms.
Insights
Somatic copy number alterations (SCNAs) disrupt microRNA (miRNA) networks in cancer. This study identifies driver miRNAs and their roles in breast cancer subtypes, revealing new pathogenic mechanisms for cancer genome interpretation.
Area of Science:
- Genomics
- Cancer Biology
- Molecular Oncology
Background:
- MicroRNAs (miRNAs) are crucial in cancer development and regulate competing endogenous RNA (ceRNA) networks.
- Somatic copy number alterations (SCNAs) can disrupt miRNA expression and unbalance ceRNA networks.
- The specific impact of miRNA SCNAs on cancer progression remains incompletely understood.
Purpose of the Study:
- To develop a method for identifying driver miRNAs affected by SCNAs.
- To elucidate the functional roles of these driver miRNAs in cancer.
- To analyze SCNA-driven ceRNA networks and their impact on cancer hallmarks.
Main Methods:
- Integration of miRNA SCNA profiles, miRNA-target relationships, and expression data (miRNA, mRNA, lncRNA).
- Application of the method to 813 TCGA breast cancer (BRCA) samples.
- Construction of dynamic ceRNA networks based on identified driver miRNAs and SCNA interference patterns.
Main Results:
- Identification of 29 driver miRNAs whose SCNAs impact their expression and target regulation.
- Discovery of three distinct patterns of SCNA interference in miRNA-mediated ceRNA networks.
- Characterization of a new BRCA subtype associated with amplification of four specific miRNAs (e.g., has-miR-30d-3p) on chromosome 8q24, linked to poor prognosis and hallmark dysfunction.
Conclusions:
- The developed method effectively identifies driver miRNAs and their SCNA-driven functions.
- Findings provide insights into cancer genome interpretation and pathogenic mechanisms.
- Driver miRNA SCNAs exhibit cancer-specific roles in regulating cancer hallmarks.
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