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A miR-15a related polymorphism affects NSCLC prognosis via altering ERCC1 repair to platinum-based chemotherapy
Ping Xue1, Guopei Zhang1, Hongchao Zhang1
1Department of Toxicology, School of Public Health, China Medical University, Shenyang, China.
Abstract:
Platinum-based chemotherapy is regarded as a preferential curative-intent option for non-small cell lung cancer (NSCLC), while the acquired drug resistance has become a major obstacle that limits its clinical application. Since the repair efficiency of tumour cells to platinum-DNA adducts plays a crucial role in chemotherapy resistance, we aimed to explore whether several meaningful polymorphisms of DNA repair genes were associated with the benefits of platinum-based chemotherapy in NSCLC patients. Firstly, six single nucleotide polymorphisms (SNPs) located in the 3'untranslated region (3'UTR) of three DNA repair genes were detected in 246 NSCLC patients receiving platinum-based chemotherapy and analysed the correlation of these candidate SNPs with the overall survival. Cox proportional hazard model showed that NSCLC patients carrying ERCC1 rs3212986 AA genotype had a shorter overall survival compared to those with CC. Mechanistically, we performed tumour chemosensitivity assay to observe the convincing linkage of rs3212986 polymorphism with ERCC1 expression and cisplatin sensitivity. The subsequent in vitro experiments identified that rs3212986 polymorphism altered the post-transcriptional regulation of ERCC1 via affecting the binding of miR-15a, and further changed the sensitivity to platinum analogue. It reminded that patients carrying ERCC1 rs3212986 CC homozygote were expected to respond better to platinum-based chemotherapy due to a lower expression of ERCC1. Compared with previous studies, our current comprehensive study suggested that rs3212986, a 3'UTR polymorphism in ERCC1, might have clinical relevance in predicting the prognosis of NSCLC patients receiving platinum-based chemotherapy.
Insights
A specific DNA repair gene polymorphism (ERCC1 rs3212986) impacts non-small cell lung cancer (NSCLC) patient survival. The CC genotype is linked to better outcomes with platinum-based chemotherapy, suggesting its use in predicting treatment response.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Platinum-based chemotherapy is a primary treatment for non-small cell lung cancer (NSCLC).
- Acquired drug resistance significantly limits the efficacy of platinum-based chemotherapy in NSCLC.
- DNA repair efficiency in tumor cells is critical in developing chemotherapy resistance.
Purpose of the Study:
- To investigate the association between DNA repair gene polymorphisms and the effectiveness of platinum-based chemotherapy in NSCLC patients.
- To identify specific single nucleotide polymorphisms (SNPs) that correlate with overall survival in NSCLC patients undergoing chemotherapy.
Main Methods:
- Genotyping of six SNPs in the 3' untranslated region (3'UTR) of three DNA repair genes in 246 NSCLC patients.
- Correlation analysis of candidate SNPs with overall survival using Cox proportional hazard models.
- Tumor chemosensitivity assays and in vitro experiments to elucidate the functional impact of the ERCC1 rs3212986 polymorphism on gene expression and drug sensitivity.
Main Results:
- NSCLC patients with the ERCC1 rs3212986 AA genotype exhibited shorter overall survival compared to those with the CC genotype.
- The rs3212986 polymorphism demonstrated a clear link with ERCC1 expression levels and sensitivity to cisplatin.
- In vitro studies confirmed that the rs3212986 polymorphism affects ERCC1 post-transcriptional regulation by influencing miR-15a binding, altering platinum analogue sensitivity.
Conclusions:
- The ERCC1 rs3212986 polymorphism, located in the 3'UTR, is associated with overall survival in NSCLC patients receiving platinum-based chemotherapy.
- Patients with the ERCC1 rs3212986 CC genotype are predicted to have a better response to platinum-based chemotherapy due to lower ERCC1 expression.
- This SNP may serve as a valuable biomarker for predicting the prognosis of NSCLC patients undergoing platinum-based treatment.
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