Ghannam Suzan F, Makhlouf Shorouk, Alsaleem Mansour, Rutland Catrin Sian, Allegrucci Cinzia, Mongan Nigel P, Rakha Emad A
Academic Unit for Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, United Kingdom; Department of Histology and Cell Biology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt; Nottingham Breast Cancer Research Centre, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom.
Academic Unit for Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, United Kingdom; Department of Pathology, Faculty of Medicine, Assiut University, Assiut, Egypt.
Mod Pathol. 2024 Dec;37(12):100607. doi: 10.1016/j.modpat.2024.100607. Epub 2024 Aug 30.
The tumor microenvironment plays a key role in tumor progression. The proportion of the stroma-to-tumor cells (stroma-tumor ratio [STR]) has a variable prognostic significance in breast cancer (BC) molecular classes. In this study, we evaluated the mechanisms of stroma formation and composition in different molecular subtypes, which could explain the different prognostic values. This study interrogated 2 large well-characterized BC cohorts. Firstly, an in-house BC cohort (n = 822) encompassing all BC molecular subtypes from the Nottingham series was used. In each subtype, stromal assessment was carried out, and tumors were assigned to 2 groups: high and low STR, and further correlation with tumor characteristics and patient outcomes was investigated. The contribution of tumor-infiltrating lymphocytes (TILs) to the stroma has also been studied. Secondly, the public domain data set (The Cancer Genome Atlas data [TCGA], n = 978) was used as a validation cohort and for differential gene expression (DGE) analysis. DGE was performed to identify a set of genes associated with high STR in the 3 main molecular subtypes. High STR was associated with favorable patient outcomes in the whole cohort and in the luminal subtype, whereas high STR showed an association with poor outcomes in triple-negative BC (TNBC). No association with outcome was found in the HER2 enriched BC. DGE analysis identified various pathways in luminal and TNBC subtypes, with immune upregulation and hypoxia pathways enriched in TNBC, and pathways related to fibrosis and stromal remodeling enriched in the luminal group instead. Low STR accompanied by high TILs was shown to carry the most favorable prognosis in TNBC. In line with the DGE results, TILs played a major prognostic role in the stroma of TNBC but not in the luminal or HER2-enriched subtypes. The underlying molecular mechanisms and composition of the stroma in BC are variable in the molecular subtypes and explain the difference in its prognostic significance.
肿瘤微环境在肿瘤进展中起关键作用。基质与肿瘤细胞的比例（基质 - 肿瘤比[STR]）在乳腺癌（BC）分子分型中具有不同的预后意义。在本研究中，我们评估了不同分子亚型中基质形成和组成的机制，这可以解释不同的预后价值。本研究调查了2个特征明确的大型BC队列。首先，使用了一个内部BC队列（n = 822），该队列涵盖了诺丁汉系列中的所有BC分子亚型。在每个亚型中，进行了基质评估，并将肿瘤分为两组：高STR组和低STR组，并进一步研究了其与肿瘤特征和患者预后的相关性。还研究了肿瘤浸润淋巴细胞（TILs）对基质的贡献。其次，公共领域数据集（癌症基因组图谱数据[TCGA]，n = 978）用作验证队列并进行差异基因表达（DGE）分析。进行DGE分析以鉴定与3种主要分子亚型中高STR相关的一组基因。在整个队列和管腔亚型中，高STR与患者的良好预后相关，而在三阴性乳腺癌（TNBC）中，高STR与不良预后相关。在HER2富集型BC中未发现与预后相关。DGE分析确定了管腔和TNBC亚型中的各种途径，免疫上调和缺氧途径在TNBC中富集，而与纤维化和基质重塑相关的途径在管腔组中富集。在TNBC中，低STR伴高TILs显示出最有利的预后。与DGE结果一致，TILs在TNBC的基质中起主要预后作用，但在管腔或HER2富集亚型中不起作用。BC中基质的潜在分子机制和组成在分子亚型中各不相同，并解释了其预后意义的差异。
