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LobSig is a multigene predictor of outcome in invasive lobular carcinoma
npj Breast Cancer ( IF 5.9 ) Pub Date : 2019-06-27 , DOI: 10.1038/s41523-019-0113-y
Amy E. McCart Reed , Samir Lal , Jamie R. Kutasovic , Leesa Wockner , Alan Robertson , Xavier M. de Luca , Priyakshi Kalita-de Croft , Andrew J. Dalley , Craig P. Coorey , Luyu Kuo , Kaltin Ferguson , Colleen Niland , Gregory Miller , Julie Johnson , Lynne E. Reid , Renique Males , Jodi M. Saunus , Georgia Chenevix-Trench , Lachlan Coin , Sunil R. Lakhani , Peter T. Simpson

Invasive lobular carcinoma (ILC) is the most common special type of breast cancer, and is characterized by functional loss of E-cadherin, resulting in cellular adhesion defects. ILC typically present as estrogen receptor positive, grade 2 breast cancers, with a good short-term prognosis. Several large-scale molecular profiling studies have now dissected the unique genomics of ILC. We have undertaken an integrative analysis of gene expression and DNA copy number to identify novel drivers and prognostic biomarkers, using in-house (n = 25), METABRIC (n = 125) and TCGA (n = 146) samples. Using in silico integrative analyses, a 194-gene set was derived that is highly prognostic in ILC (P = 1.20 × 10−5)—we named this metagene ‘LobSig’. Assessing a 10-year follow-up period, LobSig outperformed the Nottingham Prognostic Index, PAM50 risk-of-recurrence (Prosigna), OncotypeDx, and Genomic Grade Index (MapQuantDx) in a stepwise, multivariate Cox proportional hazards model, particularly in grade 2 ILC cases (χ2, P = 9.0 × 10−6), which are difficult to prognosticate clinically. Importantly, LobSig status predicted outcome with 94.6% accuracy amongst cases classified as ‘moderate-risk’ according to Nottingham Prognostic Index in the METABRIC cohort. Network analysis identified few candidate pathways, though genesets related to proliferation were identified, and a LobSig-high phenotype was associated with the TCGA proliferative subtype (χ2, P < 8.86 × 10−4). ILC with a poor outcome as predicted by LobSig were enriched with mutations in ERBB2, ERBB3, TP53, AKT1 and ROS1. LobSig has the potential to be a clinically relevant prognostic signature and warrants further development.



中文翻译:

LobSig是浸润性小叶癌预后的多基因预测因子

侵袭性小叶癌(ILC)是最常见的特殊类型的乳腺癌,其特征在于E-钙粘蛋白的功能丧失,导致细胞粘附缺陷。ILC通常表现为雌激素受体阳性的2级乳腺癌,短期预后良好。现在,一些大规模的分子谱研究已经剖析了ILC的独特基因组学。我们使用内部(n  = 25),METABRIC(n  = 125)和TCGA(n  = 146)样本对基因表达和DNA拷贝数进行了综合分析,以确定新的驱动因素和预后生物标志物。使用计算机整合分析,得出了194个基因集,在ILC中具有高度预后性(P  = 1.20×10 -5)—我们将此元基因命名为“ LobSig”。在评估10年的随访期后,LobSig在逐步的多变量Cox比例风险模型中,尤其是在2级中,胜过诺丁汉预后指数,PAM50复发风险(Prosigna),OncotypeDx和基因组等级指数(MapQuantDx)。 ILC例(χ 2P  = 9.0×10 -6),这是难以临床预言。重要的是,根据METABRIC队列中的诺丁汉预后指数,在被分类为“中度风险”的病例中,LobSig的状态预测结果的准确性为94.6%。网络分析确定了很少的候选途径,尽管鉴定了与增殖相关的基因组,并且LobSig高表型与TCGA增殖亚型相关(χ2P  <8.86×10 -4。如LobSig所预测的,结果较差的ILC富含ERBB2ERBB3TP53AKT1ROS1的突变。LobSig有可能成为临床相关的预后标志,并有待进一步开发。

更新日期:2019-06-27
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