■作为全球最常见的恶性肿瘤之一,乳腺癌(BC)表现出高度的分子表型异质性。关于DNA损伤修复(DDR)的不断发展的观点是,它具有特定的背景和异质性,但其在BC中的作用尚不清楚。
■转录组学的多维数据,基因组学,获得了单细胞转录组谱分析来表征BC的DDR相关特征。我们基于分子标签数据库(MSigDB)数据库和先前的研究收集了276个DDR相关基因。我们获得的公共数据集包括SCAN-B数据集(GEO:GSE96058),METABRIC数据库,和TCGA-BRCA数据库。相应的存储库,如转录组学,基因组学,和临床信息也被下载。我们选择了来自GEO的scRNA-seq数据:GSE176078、GSE114727、GSE161529和GSE158724。提取来自GEO:GSE176078、GSE18728、GSE5462、GSE20181和GSE130788的大量RNA-seq数据用于独立分析。
■DDR分类是在SCAN-B数据集(GEO:GSE96058)和METABRIC数据库中构建的,在BC患者中,有两个具有不同临床和分子特征的簇:DDR抑制簇和DDR活性簇.发现DDR抑制簇中的肿瘤具有较高的存活率,而那些具有DDR激活簇的人往往具有较差的预后和临床攻击行为。DDR分类在TCGA-BRCA队列中进行了验证,并显示出相似的结果。我们还发现两个簇在基因组水平上具有不同的途径活性。基于这些队列中不同表达基因的交集,我们发现PRAME可能在DDR中起着至关重要的作用。然后通过建立DDR评分来实现DDR分类,这通过多层队列分析得到了验证。此外,我们的结果显示,在单细胞水平,恶性细胞对DDR评分的贡献大于非恶性细胞.特别是,在具有可区分特征的免疫细胞中,具有免疫抑制特性的免疫细胞(如FOXP3+CD4+T细胞)表现出更高的DDR评分.
■集体,这项研究对BC中DDR异质性进行了一般性分析,并提供了对独特DDR特征的个体化分子和临床病理机制的理解.
As one of the most common malignancies worldwide, breast cancer (BC) exhibits high heterogeneity of molecular phenotypes. The evolving view regarding DNA damage repair (DDR) is that it is context-specific and heterogeneous, but its role in BC remains unclear.
Multi-dimensional data of transcriptomics, genomics, and single-cell transcriptome profiling were obtained to characterize the DDR-related features of BC. We collected 276 DDR-related genes based on the Molecular Signature Database (MSigDB) database and previous studies. We acquired public datasets included the SCAN-B dataset (GEO: GSE96058), METABRIC database, and TCGA-BRCA database. Corresponding repositories such as transcriptomics, genomics, and clinical information were also downloaded. We selected scRNA-seq data from GEO: GSE176078, GSE114727, GSE161529, and GSE158724. Bulk RNA-seq data from GEO: GSE176078, GSE18728, GSE5462, GSE20181, and GSE130788 were extracted for independent analyses.
The DDR classification was constructed in the SCAN-B dataset (GEO: GSE96058) and METABRIC database, Among BC patients, there were two clusters with distinct clinical and molecular characteristics: the DDR-suppressed cluster and the DDR-active cluster. A superior survival rate is found for tumors in the DDR-suppressed cluster, while those with the DDR-activated cluster tend to have inferior prognoses and clinically aggressive behavior. The DDR classification was validated in the TCGA-BRCA cohort and shown similar results. We also found that two clusters have different pathway activities at the genomic level. Based on the intersection of the different expressed genes among these cohorts, we found that
PRAME might play a vital role in DDR. The DDR classification was then enabled by establishing a DDR score, which was verified through multilayer cohort analysis. Furthermore, our results revealed that malignant cells contributed more to the DDR score at the single-cell level than nonmalignant cells. Particularly, immune cells with immunosuppressive properties (such as FOXP3+ CD4+ T cells) displayed higher DDR scores among those with distinguishable characteristics.
Collectively, this study performs general analyses of DDR heterogeneity in BC and provides insight into the understanding of individualized molecular and clinicopathological mechanisms underlying unique DDR profiles.