Aleskandarany Mohammed A, Sonbul Sultan, Surridge Rachel, Mukherjee Abhik, Caldas Carlos, Diez-Rodriguez Maria, Ashankyty Ibraheem, Albrahim Khalil I, Elmouna Ahmed M, Aneja Ritu, Martin Stewart G, Ellis Ian O, Green Andrew R, Rakha Emad A
Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham NG5 1PB, UK.
Pathology Department, Faculty of Medicine, Menoufyia University, Menoufyia 110532, Egypt.
Br J Cancer. 2017 Oct 10;117(8):1176-1184. doi: 10.1038/bjc.2017.261. Epub 2017 Aug 22.
The prognostic value of lymphovascular invasion (LVI) in breast cancer (BC) has been demonstrated in several independent studies. However, identification of driver molecules for LVI remains a challenging task. Large-scale transcriptomic profiling of histologically validated LVI can potentially identify genes that regulate LVI.
Integrative bio-informatics analyses of the METABRIC study were performed utilising a subset of strictly defined LVI using histological and immunohistochemical (IHC) criteria. ARHGAP18 was among the top differentially expressed genes between LVI+ and LVI- BC with a 1.8-fold change. The prognostic impact of ARHGAP18 gene expression was assessed in the METABRIC data set (n=1980) and externally validated using the online BC gene expression data sets utilising bc-GenExMiner v4.0 (n=2016). Subsequently, ARHGAP18 protein expression was assessed on a large cohort of invasive BC (n=959) with long-term follow-up using IHC.
Pooled analysis of ARHGAP18 mRNA expression showed that overexpression was associated with better outcome (P<0.001, hazard ratio (HR)=0.82, 95% CI 0.75-0.90). ARHGAP18 protein was expressed in the cytoplasm and nuclei of the tumour cells and its expression was positively associated with good prognostic variables. Lack of cytoplasmic expression showed associations with LVI (P=0.006), epithelial-mesenchymal transition and the HER+ subtype (P=0.01). Loss of nuclear expression was associated with higher grade, HER2+ and high Ki67LI (P=0.001). Cytoplasmic and nuclear expression showed a positive association with improved survival independent of other variables (P=0.01, HR=0.74, 95% CI 0.60-87).
ARHGAP18 expression at transcriptomic and protein levels is associated with improved patients' outcomes whose deregulation may play a role in tumour progression and the development of LVI in BC. Further assessment of its potential therapeutic value in BC is warranted.
多项独立研究已证实淋巴管浸润（LVI）在乳腺癌（BC）中的预后价值。然而，确定LVI的驱动分子仍然是一项具有挑战性的任务。对经组织学验证的LVI进行大规模转录组分析可能会识别出调控LVI的基因。
利用组织学和免疫组织化学（IHC）标准对严格定义的LVI子集进行METABRIC研究的综合生物信息学分析。ARHGAP18是LVI阳性和LVI阴性BC之间差异表达最显著的基因之一，变化倍数为1.8倍。在METABRIC数据集中（n = 1980）评估ARHGAP18基因表达的预后影响，并使用bc-GenExMiner v4.0在线BC基因表达数据集（n = 2016）进行外部验证。随后，使用IHC对一大组具有长期随访的浸润性BC（n = 959）进行ARHGAP18蛋白表达评估。
ARHGAP18 mRNA表达的汇总分析表明，过表达与更好的预后相关（P < 0.001，风险比（HR）= 0.82，95%可信区间0.75 - 0.90）。ARHGAP18蛋白在肿瘤细胞的细胞质和细胞核中表达，其表达与良好的预后变量呈正相关。缺乏细胞质表达与LVI（P = 0.006）、上皮-间质转化和HER +亚型（P = 0.01）相关。核表达缺失与更高分级、HER2 +和高Ki67LI相关（P = 0.001）。细胞质和核表达与独立于其他变量的生存改善呈正相关（P = 0.01，HR = 0.74，95%可信区间0.60 - 87）。
ARHGAP18在转录组和蛋白水平的表达与患者预后改善相关，其失调可能在BC的肿瘤进展和LVI发展中起作用。有必要进一步评估其在BC中的潜在治疗价值。
