Identification of three subtypes of triple-negative breast cancer with potential therapeutic implications
Identification of three subtypes of triple-negative breast cancer with potential therapeutic implications
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DOI：
10.1186/s13058-019-1148-6
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发表时间：
2019-05-17
影响因子：
7.4
通讯作者：
Campone, Mario
中科院分区：
文献类型：
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作者：
Jezequel, Pascal;Kerdraon, Olivier;Campone, Mario
背景异质性和缺乏靶向治疗是三阴性乳腺癌（TNBC）精准治疗的两个主要障碍，因此，需要分子分型和治疗途径的识别来优化医疗护理。本研究的目的是定义具有临床相关性的稳健 TNBC 亚型。方法通过 DNA 芯片在由 238 名患者组成的内部 TNBC 队列中进行基因表达谱分析。此外，使用相同DNA芯片获得的外部数据（n=257）用于验证。模糊聚类之后是聚类的功能注释。免疫组化用于确认转录组学结果：CD138和CD20分别用于检测浆细胞和B淋巴细胞浸润； MECA79 和 CD31 用于三级淋巴结构； UCHL1/PGP9.5 和 S100 用于神经发生。结果我们在 TNBC 中鉴定了三个分子簇：一个分子顶浆分泌 (C1) 和两个基底样富集（C2 和 C3）。 C2 呈现促肿瘤免疫反应（免疫抑制）、高神经发生（神经浸润）和高生物攻击性。相比之下，C3 表现出与三级淋巴结构中发生的完全 B 细胞分化相关的适应性免疫反应以及免疫检查点上调。通过相同方法进行的外部队列亚型证明了这些结果的稳健性。此外，通过组织学评估和免疫组织化学，在蛋白质水平上验证了浆细胞和 B 淋巴细胞浸润、三级淋巴结构和神经发生。结论我们的工作表明，TNBC 可以分为三种不同的亚型，具有明显的生物学特征，其中一些亚型可以通过特定的治疗来靶向。
BackgroundHeterogeneity and lack of targeted therapies represent the two main impediments to precision treatment of triple-negative breast cancer (TNBC), and therefore, molecular subtyping and identification of therapeutic pathways are required to optimize medical care. The aim of the present study was to define robust TNBC subtypes with clinical relevance.MethodsGene expression profiling by means of DNA chips was conducted in an internal TNBC cohort composed of 238 patients. In addition, external data (n=257), obtained by using the same DNA chip, were used for validation. Fuzzy clustering was followed by functional annotation of the clusters. Immunohistochemistry was used to confirm transcriptomics results: CD138 and CD20 were used to test for plasma cell and B lymphocyte infiltrations, respectively; MECA79 and CD31 for tertiary lymphoid structures; and UCHL1/PGP9.5 and S100 for neurogenesis.ResultsWe identified three molecular clusters within TNBC: one molecular apocrine (C1) and two basal-like-enriched (C2 and C3). C2 presented pro-tumorigenic immune response (immune suppressive), high neurogenesis (nerve infiltration), and high biological aggressiveness. In contrast, C3 exhibited adaptive immune response associated with complete B cell differentiation that occurs in tertiary lymphoid structures, and immune checkpoint upregulation. External cohort subtyping by means of the same approach proved the robustness of these results. Furthermore, plasma cell and B lymphocyte infiltrates, tertiary lymphoid structures, and neurogenesis were validated at the protein levels by means of histological evaluation and immunohistochemistry.ConclusionOur work showed that TNBC can be subcategorized in three different subtypes characterized by marked biological features, some of which could be targeted by specific therapies.