Abstract
BackgroundFusion 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.MethodsFusion 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).ResultsVacuole 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.ConclusionsThe 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.
Highlights
breast cancer (BC) is the most common type of cancer diagnosed in women worldwide [1]
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
The results suggest that high vacuole membrane protein 1 (VMP1) expression is a potential marker of poor prognosis in HER2 positive BC
Summary
BC is the most common type of cancer diagnosed in women worldwide [1]. The prognosis and treatment depend on the stage of the disease at diagnosis, the type of tumor, the grade, the proliferation status (Ki67 expression), and the expression of HER2/ERBB2 and the hormonal receptors, estrogen and progesterone receptors. Genes that support tumorigenesis most often have undergone changes that result in loss of control or changes in expression patterns Genetic rearrangements such as amplification, translocations, inversions, insertions and deletions are frequent in breast tumors. Amplified chromosomal regions are well known in breast tumors [2], the amplifications of the ERBB2 locus at 17q12 It results in the genes overexpression giving the cell the potential to bypass regulatory mechanisms and support malignant growth. We postulated that screening fusion genes could be used as a tool to identify potentially novel cancer genes that can affect 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
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