Abstract
DNA abnormalities are used in inclusion criteria of clinical trials for treatments with specific targeted molecules. MYC is one of the most powerful oncogenes and is known to be associated with triple-negative breast cancer (TNBC). Its DNA amplification is often part of the targeted DNA-sequencing panels under the assumption of reflecting upregulated signaling. However, it remains unclear if MYC DNA amplification is a surrogate of its upregulated signaling. Thus, we investigated the difference between MYC DNA amplification and mRNA high expression in TNBCs utilizing publicly available cohorts. MYC DNA amplified tumors were found to have various mRNA expression levels, suggesting that MYC DNA amplification does not always result in elevated MYC mRNA expression. Compared to other subtypes, both MYC DNA amplification and mRNA high expression were more frequent in the TNBCs. MYC mRNA high expression, but not DNA amplification, was significantly associated with worse overall survival in the TNBCs. The TNBCs with MYC mRNA high expression enriched MYC target genes, cell cycle related genes, and WNT/β-catenin gene sets, whereas none of them were enriched in MYC DNA amplified TNBCs. In conclusion, MYC mRNA high expression, but not DNA amplification, reflects not only its upregulated signaling pathway, but also clinical significance in TNBCs.
Highlights
Clinical targeted DNA-sequencing to detect genomic alterations, including mutation and copy number alterations, has become routine in clinical practice for multiple cancers
We aimed to investigate the clinical significance of MYC DNA amplification and mRNA high expression in triple-negative breast cancer (TNBC) through the use of two large publicly available cohorts, The Cancer Genome Atlas (TCGA) [17] and METABRIC [18]
We found that MYC targets gene sets (v1: Normalized Enrichment Score (NES) = 2.183, p < 0.001; v2: NES = 2.194, p < 0.001) [21] as well as cell cycle related gene sets that are known to be regulated by MYC [22,23] (E2F targets: NES = 1.971, p = 0.013; G2/M check point: NES = 1.867, p = 0.018) were enriched in the MYC mRNA high expressing TNBCs (Figure 5B)
Summary
Clinical targeted DNA-sequencing to detect genomic alterations, including mutation and copy number alterations, has become routine in clinical practice for multiple cancers. MYC is one of the most powerful oncogenes encoding transcription factor. MYC forms a heterodimer with MYC-associated factor X and binds to the E box of its target genes to regulate gene expressions [1]. MYC regulates the expression of many genes involved in cellular proliferation, transformation, angiogenesis, and cell cycle control, such as the E2F family and the G2/M check point genes [1,2,3]. MYC transcription is strictly regulated by many signaling pathways including WNT/β -catenin, Notch, and TGF-β pathways [1]. MYC is one of the most dysregulated oncogenes, including translocation and copy number alteration, in various types of cancers [4,6,7,8,9,10]. MYC DNA amplification is part of the eligibility criteria of some clinical trials because drugs that target the MYC pathway, such as ibrutinib and prexasertib, have been developed
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