三阴性乳腺癌化疗敏感性的基因组指数。

Genomic Index of Sensitivity to Chemotherapy for Triple Negative Breast Cancer.

机构信息

Department of Applied Sciences, Parul University, Vadodara, India.

Parul Sevashram Hospital, Parul University, Vadodara, India.

出版信息

Asian Pac J Cancer Prev. 2023 Jun 1;24(6):2043-2053. doi: 10.31557/APJCP.2023.24.6.2043.

DOI:10.31557/APJCP.2023.24.6.2043

PMID:37378935

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10505887/

Abstract

OBJECTIVE

Patients with triple-negative breast cancer (TNBC) frequently develop resistance to chemotherapy. Studies have shown that microRNAs (miRNAs) are often aberrantly expressed in TNBC and are associated with drug resistance. However, a prognostic strategy that correlates miRNAs with chemotherapy resistance remains largely unknown.

METHODS

To identify breast cancer chemoresistance-associated miRNAs, the miRNA microarray dataset GSE71142 was downloaded from the Gene Expression Omnibus database. Differentially expressed miRNAs (DE-miRNAs) in chemoresistant groups were identified using the LIMMA package in R. Potential target genes were predicted using the miRTarBase 9. Functional and pathway enrichment analyses was done using WebGestalt. A protein-protein interaction network was visualized using Cytoscape software. The top six hub genes regulated by DE-miRNAs were identified using the random forest model. The chemotherapy resistance index (CRI) in TNBC was defined as sum of the median expression levels of the top six hub genes. The association of CRI with distant relapse risk was evaluated using point-biserial correlation coefficient in the validation cohorts of patients with TNBC. The correlation between CRI and cumulative hazard rate was estimated using the Cox model, and the predicted rate of distant relapse was obtained from the Breslow-type estimator of the survival function. All statistical computations were performed using Origin2019b.

RESULTS

A total of 12 DE-miRNAs were screened, including six upregulated and six downregulated miRNAs in chemoresistant breast cancer tissues compared with chemosensitive tissues. Based on fold changes, miR-214-3p, miR-4758-3p, miR-200c-3p, miR-4254, miR-140-3p, and miR-24-3p were the top six most upregulated miRNAs, whereas miR-142-5p, miR-146-5p, miR-1268b, miR-1275, miR-4447, and miR-4472 were the top six most downregulated miRNAs. The top three hub genes for upregulated miRNAs were RAC1, MYC, and CCND1 and for downregulated miRNAs were IL-6, SOCS1, and PDGFRA. CRI was significantly associated with the risk of distant relapse.

CONCLUSION

CRI predicted survival benefits with reduced hazard rate.

摘要

目的

三阴性乳腺癌（TNBC）患者常对化疗产生耐药性。研究表明，miRNAs 在 TNBC 中常发生异常表达，并与耐药性相关。然而，将 miRNAs 与化疗耐药性相关联的预后策略在很大程度上仍然未知。

方法

为了鉴定与乳腺癌化疗耐药相关的 miRNAs，从基因表达综合数据库（Gene Expression Omnibus database）中下载 miRNA 微阵列数据集 GSE71142。使用 R 中的 LIMMA 包鉴定化疗耐药组中差异表达的 miRNAs（DE-miRNAs）。使用 miRTarBase 9 预测潜在的靶基因。使用 WebGestalt 进行功能和通路富集分析。使用 Cytoscape 软件可视化蛋白质-蛋白质相互作用网络。使用随机森林模型鉴定受 DE-miRNAs 调控的前六个枢纽基因。在 TNBC 的验证队列中，将 TNBC 的化疗耐药指数（CRI）定义为前六个枢纽基因中位表达水平的总和。使用点双列相关系数评估 CRI 与远处复发风险的相关性。使用 Cox 模型估计 CRI 与累积危险率之间的相关性，并从生存函数的 Breslow 型估计器获得远处复发的预测率。所有统计计算均使用 Origin2019b 进行。

结果

共筛选出 12 个 DE-miRNAs，与化疗敏感组织相比，化疗耐药的乳腺癌组织中存在 6 个上调和 6 个下调的 miRNAs。基于倍数变化，miR-214-3p、miR-4758-3p、miR-200c-3p、miR-4254、miR-140-3p 和 miR-24-3p 是上调最明显的前 6 个 miRNAs，而 miR-142-5p、miR-146-5p、miR-1268b、miR-1275、miR-4447 和 miR-4472 是下调最明显的前 6 个 miRNAs。上调 miRNAs 的前三个枢纽基因为 RAC1、MYC 和 CCND1，下调 miRNAs 的前三个枢纽基因为 IL-6、SOCS1 和 PDGFRA。CRI 与远处复发的风险显著相关。