State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
Department of Breast Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
Breast Cancer Res Treat. 2019 Jun;175(2):459-472. doi: 10.1007/s10549-019-05135-w. Epub 2019 Feb 19.
Breast cancer is a heterogeneous disease, and although advances in molecular subtyping have been achieved in recent years, most subtyping strategies target individual genes independent of one another and primarily concentrate on proliferative markers. The contributions of biological processes and immune patterns have been neglected in breast cancer subtype stratification.
We performed a gene set variation analysis to simplify the information on biological processes using hallmark terms and to decompose immune cell data using the immune cell gene terms on 985 breast invasive ductal/lobular carcinoma RNAseq samples in the TCGA database.
The samples were gathered into three clusters following implementation of the t-SNE and DBSCAN algorithms and were categorized as 'hallmark-tsne' subtypes. Here, we identified a high-risk luminal A dominant breast cancer subtype (C3) that displayed increased motility, cancer stem cell-like features, a higher expression of hormone/luminal-related genes, a lower expression of proliferation-related genes and immune dysfunction. With regard to immune dysfunction, we observed that the motility-increased C3 subtype exhibited high granulocyte colony stimulating factor (G-CSF) expression accompanied by neutrophil aggregation. Cancer cells that produce high levels of G-CSF can stimulate neutrophils to form neutrophil extracellular traps, which promote cancer cell migration. This finding sheds light on one potential explanation for why the C3 subtype correlates with poor prognosis.
The hallmark-tsne subtypes confirmed again that even the luminal A subtype is heterogeneous and can be further subdivided. The biological processes and immune heterogeneity of breast cancer must be understood to facilitate the improvement of clinical treatments.
乳腺癌是一种异质性疾病，尽管近年来在分子亚分型方面取得了进展，但大多数亚分型策略都是针对独立的单个基因，主要集中在增殖标志物上。在乳腺癌亚型分层中，生物过程和免疫模式的贡献被忽视了。
我们使用标志性术语对生物过程进行了基因集变异分析（gene set variation analysis），使用免疫细胞基因术语对 TCGA 数据库中 985 例乳腺浸润性导管/小叶癌 RNAseq 样本中的免疫细胞数据进行了分解。
在实施 t-SNE 和 DBSCAN 算法后，这些样本被分为三个聚类，并被归类为“标志性-t-SNE”亚型。在这里，我们发现了一种高风险的腔 A 主导型乳腺癌亚型（C3），其表现出更高的运动性、癌症干细胞样特征、更高的激素/腔相关基因表达、更低的增殖相关基因表达和免疫功能障碍。关于免疫功能障碍，我们观察到运动性增加的 C3 亚型表现出高水平的粒细胞集落刺激因子（G-CSF）表达，伴随着中性粒细胞聚集。产生高水平 G-CSF 的癌细胞可以刺激中性粒细胞形成中性粒细胞细胞外陷阱，从而促进癌细胞迁移。这一发现为 C3 亚型与预后不良相关的原因提供了一个潜在的解释。
标志性-t-SNE 亚型再次证实，即使是腔 A 亚型也是异质性的，可以进一步细分。为了促进临床治疗的改善，必须了解乳腺癌的生物学过程和免疫异质性。
