Dataset Information

Identifying the driver miRNAs with somatic copy number alterations driving dysregulated ceRNA networks in cancers.

ABSTRACT:

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.

SUBMITTER: Dou R

PROVIDER: S-EPMC10666415 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Publications

Identifying the driver miRNAs with somatic copy number alterations driving dysregulated ceRNA networks in cancers.

Dou Renjie R Kang Shaobo S Yang Huan H Zhang Wanmei W Zhang Yijing Y Liu Yuanyuan Y Ping Yanyan Y Pang Bo B

Biology direct 20231122 1

<h4>Background</h4>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.<h4>Methods</h4>In this study, we proposed a method to dissect the functional ro ...[more]

PMID: 37993951

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Project description:Intratumour heterogeneity fuels carcinogenesis and allows circumventing specific targeted therapies. HER2 gene amplification is associated with poor outcome in invasive breast cancer. Heterogeneous HER2 amplification has been described in 5-41% of breast cancers. Here, we investigated the genetic differences between HER2-positive and HER2-negative admixed breast cancer components. We performed an in-depth analysis to explore the potential heterogeneity in the somatic mutational landscape of each individual tumour component. Formalin-fixed, paraffin-embedded breast cancer tissue of ten patients with at least one HER2-negative and at least one HER2-positive component was microdissected. Targeted next-generation sequencing was performed using a customized 53-gene panel. Somatic mutations and copy number variations were analysed. Overall, the tumours showed a heterogeneous distribution of 12 deletions, 9 insertions, 32 missense variants and 7 nonsense variants in 26 different genes, which are (likely) pathogenic. Three splice site alterations were identified. One patient had an EGFR copy number gain restricted to a HER2-negative in situ component, resulting in EGFR protein overexpression. Two patients had FGFR1 copy number gains in at least one tumour component. Two patients had an 8q24 gain in at least one tumour component, resulting in a copy number increase in MYC and PVT1. One patient had a CCND1 copy number gain restricted to a HER2-negative tumour component. No common alternative drivers were identified in the HER2-negative tumour components. This series of 10 breast cancers with heterogeneous HER2 gene amplification illustrates that HER2 positivity is not an unconditional prerequisite for the maintenance of tumour growth. Many other molecular aberrations are likely to act as alternative or collaborative drivers. This study demonstrates that breast carcinogenesis is a dynamically evolving process characterized by a versatile somatic mutational profile, of which some genetic aberrations will be crucial for cancer progression, and others will be mere 'passenger' molecular anomalies.

Dataset Information

Identifying the driver miRNAs with somatic copy number alterations driving dysregulated ceRNA networks in cancers.

Background

Methods

Results

Conclusions

Publications

Identifying the driver miRNAs with somatic copy number alterations driving dysregulated ceRNA networks in cancers.

Similar Datasets

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