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三阴性乳腺癌转录组特征分析——寻找潜在的基于RNA的预测生物标志物以确定化疗敏感性。

The analysis of transcriptomic signature of TNBC-searching for the potential RNA-based predictive biomarkers to determine the chemotherapy sensitivity.

作者信息

Supplitt Stanislaw, Karpinski Pawel, Sasiadek Maria, Laczmanski Lukasz, Kujawa Dorota, Matkowski Rafal, Kasprzak Piotr, Abrahamowska Mariola, Maciejczyk Adam, Iwaneczko Ewelina, Laczmanska Izabela

机构信息

Lower Silesian Oncology, Pulmonology and Hematology Center, Hirszfelda Sq. 12, 53-413, Wroclaw, Poland.

Department of Genetics, Wroclaw Medical University, Marcinkowskiego 1, 50-368, Wroclaw, Poland.

出版信息

J Appl Genet. 2025 Feb;66(1):171-182. doi: 10.1007/s13353-024-00876-x. Epub 2024 May 9.

Abstract

Neoadjuvant chemotherapy is the foundation treatment for triple-negative breast cancer (TNBC) and frequently results in pathological complete response (pCR). However, there are large differences in clinical response and survival after neoadjuvant chemotherapy of TNBC patients. The aim was to identify genes whose expression significantly associates with the efficacy of neoadjuvant chemotherapy in patients with TNBC. Transcriptomes of 46 formalin-fixed paraffin-embedded (FFPE) tumor samples from TNBC patients were analyzed by RNA-seq by comparing 26 TNBCs with pCR versus 20 TNBCs with pathological partial remission (pPR). Subsequently, we narrowed down the list of genes to those that strongly correlated with drug sensitivity of 63 breast cancer cell lines based on Dependency Map Consortium data re-analysis. Furthermore, the list of genes was limited to those presenting specific expression in breast tumor cells as revealed in three large published single-cell RNA-seq breast cancer datasets. Finally, we analyzed which of the selected genes were significantly associated with overall survival (OS) in TNBC TCGA dataset. A total of 105 genes were significantly differentially expressed in comparison between pPR versus pCR. As revealed by PLSR analysis in breast cancer cell lines, out of 105 deregulated genes, 42 were associated with sensitivity to docetaxel, doxorubicin, paclitaxel, and/or cyclophosphamide. We found that 24 out of 42 sensitivity-associated genes displayed intermediate or strong expression in breast malignant cells using single-cell RNAseq re-analysis. Finally, 10 out of 24 genes were significantly associated with overall survival in TNBC TCGA dataset. Our RNA-seq-based findings suggest that there might be transcriptomic signature consisted of 24 genes specifically expressed in tumor malignant cells for predicting neoadjuvant response in FFPE samples from TNBC patients prior to treatment initiation. Additionally, nine out of 24 genes were potential survival predictors in TNBC. This group of 24 genes should be further investigated for its potential to be translated into a predictive test(s).

摘要

新辅助化疗是三阴性乳腺癌(TNBC)的基础治疗方法,且常常导致病理完全缓解(pCR)。然而,TNBC患者新辅助化疗后的临床反应和生存率存在很大差异。本研究旨在鉴定其表达与TNBC患者新辅助化疗疗效显著相关的基因。通过RNA测序分析了46例TNBC患者福尔马林固定石蜡包埋(FFPE)肿瘤样本的转录组,将26例达到pCR的TNBC与20例病理部分缓解(pPR)的TNBC进行比较。随后,基于依赖性图谱联盟数据重新分析,我们将基因列表缩小至与63种乳腺癌细胞系药物敏感性密切相关的基因。此外,根据三个已发表的大型单细胞RNA测序乳腺癌数据集,将基因列表限定为在乳腺肿瘤细胞中呈现特异性表达的基因。最后,我们分析了所选基因中哪些与TNBC TCGA数据集中的总生存期(OS)显著相关。与pPR相比,共有105个基因存在显著差异表达。正如在乳腺癌细胞系中通过偏最小二乘回归(PLSR)分析所揭示的,在105个失调基因中,有42个与多西他赛、阿霉素、紫杉醇和/或环磷酰胺的敏感性相关。通过单细胞RNA测序重新分析,我们发现42个与敏感性相关的基因中有24个在乳腺恶性细胞中呈中等或强表达。最后,24个基因中的10个与TNBC TCGA数据集中的总生存期显著相关。我们基于RNA测序的研究结果表明,可能存在一个由24个在肿瘤恶性细胞中特异性表达的基因组成的转录组特征,用于预测TNBC患者治疗开始前FFPE样本中的新辅助反应。此外,24个基因中有9个是TNBC潜在的生存预测指标。这组24个基因的潜在价值应进一步研究,以便转化为预测性检测方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bfea/11761126/1dd131070af1/13353_2024_876_Sch1_HTML.jpg

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