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Analysis of Combinatorial miRNA Treatments to Regulate Cell Cycle and Angiogenesis
Published on: March 30, 2019
MicroRNA-Related DNA Repair/Cell-Cycle Genes Independently Associated With Relapse After Radiation Therapy for Early
Harriet E Gee1, Francesca M Buffa2, Adrian L Harris2
1The Kinghorn Cancer Centre & Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; The Chris O'Brien Lifehouse, Missenden Road, Camperdown, NSW, Australia; Central Clinical School, Sydney Medical School, University of Sydney, NSW, Australia.
Purpose:
Local recurrence and distant failure after adjuvant radiation therapy for breast cancer remain significant clinical problems, incompletely predicted by conventional clinicopathologic markers. We had previously identified microRNA-139-5p and microRNA-1274a as key regulators of breast cancer radiation response in vitro. The purpose of this study was to investigate standard clinicopathologic markers of local recurrence in a contemporary series and to establish whether putative target genes of microRNAs involved in DNA repair and cell cycle control could better predict radiation therapy response in vivo.
Methods And Materials:
With institutional ethics board approval, local recurrence was measured in a contemporary, prospectively collected series of 458 patients treated with radiation therapy after breast-conserving surgery. Additionally, independent publicly available mRNA/microRNA microarray expression datasets totaling >1000 early-stage breast cancer patients, treated with adjuvant radiation therapy, with >10 years of follow-up, were analyzed. The expression of putative microRNA target biomarkers--TOP2A, POLQ, RAD54L, SKP2, PLK2, and RAG1--were correlated with standard clinicopathologic variables using 2-sided nonparametric tests, and to local/distant relapse and survival using Kaplan-Meier and Cox regression analysis.
Results:
We found a low rate of isolated local recurrence (1.95%) in our modern series, and that few clinicopathologic variables (such as lymphovascular invasion) were significantly predictive. In multiple independent datasets (n>1000), however, high expression of RAD54L, TOP2A, POLQ, and SKP2 significantly correlated with local recurrence, survival, or both in univariate and multivariate analyses (P<.001). Low RAG1 expression significantly correlated with local recurrence (multivariate, P=.008). Additionally, RAD54L, SKP2, and PLK2 may be predictive, being prognostic in radiation therapy-treated patients but not in untreated matched control individuals (n=107; P<.05).
Conclusions:
Biomarkers of DNA repair and cell cycle control can identify patients at high risk of treatment failure in those receiving radiation therapy for early breast cancer in independent cohorts. These should be further investigated prospectively, especially TOP2A and SKP2, for which targeted therapies are available.
Insights
Biomarkers related to DNA repair and cell cycle control can predict treatment failure in breast cancer patients receiving radiation therapy. Genes like TOP2A and SKP2 show promise for identifying high-risk individuals.
Area of Science:
- Oncology
- Genetics
- Radiation Oncology
Background:
- Adjuvant radiation therapy for breast cancer can lead to local recurrence and distant failure.
- Conventional clinicopathologic markers have limitations in predicting treatment outcomes.
- MicroRNAs (miRNAs) like miR-139-5p and miR-1274a have been implicated in radiation response in vitro.
Purpose of the Study:
- To evaluate standard clinicopathologic markers for local recurrence in a contemporary breast cancer cohort.
- To determine if microRNA target genes involved in DNA repair and cell cycle control can better predict radiation therapy response in vivo.
- To identify novel biomarkers for predicting treatment failure after adjuvant radiation therapy.
Main Methods:
- Analysis of local recurrence in 458 patients treated with radiation therapy post-breast-conserving surgery.
- Examination of publicly available microarray datasets (>1000 early-stage breast cancer patients) with long-term follow-up.
- Correlation of putative miRNA target gene expression (TOP2A, POLQ, RAD54L, SKP2, PLK2, RAG1) with clinicopathologic variables, local/distant relapse, and survival using statistical analyses.
Main Results:
- A low rate of isolated local recurrence (1.95%) was observed in the modern patient series.
- High expression of RAD54L, TOP2A, POLQ, and SKP2 significantly correlated with local recurrence or survival in independent datasets (n>1000).
- Low RAG1 expression was associated with increased local recurrence risk (multivariate analysis).
- RAD54L, SKP2, and PLK2 showed prognostic value specifically in radiation-treated patients, not in controls.
Conclusions:
- Biomarkers regulating DNA repair and cell cycle control can identify patients at high risk of treatment failure following radiation therapy for early breast cancer.
- These biomarkers demonstrate predictive potential across independent patient cohorts.
- TOP2A and SKP2 are particularly promising candidates for further prospective investigation, especially given the availability of targeted therapies.
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