Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, Beijing, China.
Department of Cardiac Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
Breast Cancer Res. 2024 Nov 29;26(1):172. doi: 10.1186/s13058-024-01928-0.
Breast cancer, which is the most prevalent form of cancer among women globally, encompasses various subtypes that demand distinct treatment approaches. The tumor microenvironment and immune response are of crucial significance in the development and progression of breast cancer. Nevertheless, there has been scant evidence concerning the genes within breast cancer - specific immune cells.
We utilized summary data-based Mendelian randomization (SMR) to identify genes associated with breast cancer by utilizing expression quantitative trait loci (eQTL) datasets for 14 different immune cell types and genome-wide association studies (GWAS) for overall breast cancer and its subtypes. Furthermore, colocalization analysis was carried out to evaluate whether the observed association in SMR analyses is influenced by the same causal variant. Replication analysis and bulk RNA sequencing (bulkRNA-seq) analysis were employed to validate promising immune genes as potential drug targets.
After correcting for the rate of false discovery, we discovered a total of 17 genes in 9 immune cell types that were significantly associated with overall breast cancer and its subtypes. The genes KCNN4, L3MBTL3, ZBTB38, MDM4, and TNFSF10 were identified in overall breast cancer and its subtypes. Colocalization analyses provided robust evidence in support of these associations. Notably, the KCNN4 gene in non-classical MONOcytes (MONOnc) was further validated through replication analysis and bulkRNA-seq analysis.
In summary, our research has revealed a repertoire of genes within diverse immune cells associated with breast cancer. KCNN4 gene in non-classical MONOcytes (MONOnc) exhibited a negative association with overall breast cancer and its subtypes, which was identified as a potential drug target for breast cancer, opening up new avenues for therapeutic interventions.
乳腺癌是全球女性最常见的癌症类型，包括多种需要不同治疗方法的亚型。肿瘤微环境和免疫反应对乳腺癌的发展和进展至关重要。然而，关于乳腺癌特异性免疫细胞内的基因，相关证据仍然很少。
我们利用基于汇总数据的孟德尔随机化（SMR），通过使用 14 种不同免疫细胞类型的表达数量性状基因座（eQTL）数据集和全基因组关联研究（GWAS）来识别与乳腺癌相关的基因，用于整体乳腺癌及其亚型。此外，还进行了共定位分析，以评估 SMR 分析中观察到的关联是否受到相同因果变异的影响。复制分析和批量 RNA 测序（bulkRNA-seq）分析用于验证有前途的免疫基因作为潜在的药物靶点。
在纠正错误发现率后，我们在 9 种免疫细胞类型中总共发现了 17 个与整体乳腺癌及其亚型显著相关的基因。在整体乳腺癌及其亚型中发现了 KCNN4、L3MBTL3、ZBTB38、MDM4 和 TNFSF10 基因。共定位分析为这些关联提供了强有力的证据。值得注意的是，非经典 MONOcytes（MONOnc）中的 KCNN4 基因通过复制分析和批量 RNA-seq 分析得到了进一步验证。
总之，我们的研究揭示了与乳腺癌相关的多种免疫细胞中的一系列基因。非经典 MONOcytes（MONOnc）中的 KCNN4 基因与整体乳腺癌及其亚型呈负相关，被鉴定为乳腺癌的潜在药物靶点，为治疗干预开辟了新途径。
