Cell Biology Unit at the Pathology Department, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland.
The Biomedical Center, University of Iceland, Reykjavik, Iceland.
PLoS One. 2019 Aug 23;14(8):e0221413. doi: 10.1371/journal.pone.0221413. eCollection 2019.
Fusion genes result from genomic structural changes, which can lead to alterations in gene expression that supports tumor development. The aim of the study was to use fusion genes as a tool to identify new breast cancer (BC) genes with a role in BC progression.
Fusion genes from breast tumors and BC cell lines were collected from publications. RNA-Seq data from tumors and cell lines were retrieved from databanks and analyzed for fusions with SOAPfuse or the analysis was purchased. Fusion genes identified in both tumors (n = 1724) and cell lines (n = 45) were confirmed by qRT-PCR and sequencing. Their individual genes were ranked by selection criteria that included correlation of their mRNA level with copy number. The expression of the top ranked gene was measured by qRT-PCR in normal tissue and in breast tumors from an exploratory cohort (n = 141) and a validation cohort (n = 277). Expression levels were correlated with clinical and pathological factors as well as the patients' survival. The results were followed up in BC cohorts from TCGA (n = 818) and METABRIC (n = 2509).
Vacuole membrane protein 1 (VMP1) was the most promising candidate based on specific selection criteria. Its expression was higher in breast tumor tissue than normal tissue (p = 1x10-4), and its expression was significantly higher in HER2 positive than HER2 negative breast tumors in all four cohorts analyzed. High expression of VMP1 associated with breast cancer specific survival (BCSS) in cohort 1 (hazard ratio (HR) = 2.31, CI 1.27-4.18) and METABRIC (HR = 1.26, CI 1.02-1.57), and also after adjusting for HER2 expression in cohort 1 (HR = 2.03, CI 1.10-3.72). BCSS was not significant in cohort 2 or TCGA cohort, which may be due to differences in treatment regimens.
The results suggest that high VMP1 expression is a potential marker of poor prognosis in HER2 positive BC. Further studies are needed to elucidate how VMP1 could affect pathways supportive of tumorigenesis.
融合基因是基因组结构变化的结果，可导致支持肿瘤发展的基因表达改变。本研究旨在利用融合基因作为工具，鉴定在乳腺癌（BC）进展中起作用的新的 BC 基因。
从文献中收集乳腺癌肿瘤和 BC 细胞系的融合基因。从数据库中检索肿瘤和细胞系的 RNA-Seq 数据，并使用 SOAPfuse 或购买的分析进行融合分析。在肿瘤（n=1724）和细胞系（n=45）中均鉴定出的融合基因通过 qRT-PCR 和测序进行验证。根据包括其 mRNA 水平与拷贝数相关性的选择标准对其个体基因进行排序。通过 qRT-PCR 在探索性队列（n=141）和验证性队列（n=277）的正常组织和乳腺癌肿瘤中测量排名最高的基因的表达。将表达水平与临床病理因素以及患者的生存情况进行相关性分析。在 TCGA（n=818）和 METABRIC（n=2509）的 BC 队列中对结果进行随访。
根据特定的选择标准，液泡膜蛋白 1（VMP1）是最有前途的候选基因。其在乳腺癌组织中的表达高于正常组织（p=1x10-4），在所有四个分析的队列中，VMP1 在 HER2 阳性乳腺癌中的表达均显著高于 HER2 阴性乳腺癌。在队列 1 中，高 VMP1 表达与乳腺癌特异性生存（BCSS）相关（风险比（HR）=2.31，95%置信区间（CI）1.27-4.18），在 METABRIC 中也相关（HR=1.26，95%CI 1.02-1.57），并且在调整队列 1 中的 HER2 表达后也相关（HR=2.03，95%CI 1.10-3.72）。在队列 2 或 TCGA 队列中，BCSS 不显著，这可能是由于治疗方案的差异所致。
结果表明，高 VMP1 表达可能是 HER2 阳性 BC 不良预后的潜在标志物。需要进一步研究阐明 VMP1 如何影响支持肿瘤发生的途径。
