Pan-cancer analysis for oncogenes and mechanisms of their upregulation

Abstract

Abstract Background Each tumor has a unique molecular portrait, nevertheless, there are also a number of genetic and epigenetic aberrations that are inherent to the groups of epithelial tumors of different localizations. Our research was aimed at the identification of genes with significantly increased expression (potential oncogenes) in multiple cancer types and determination of mechanisms of their upregulation. Methods Bioinformatics analysis was performed using our CrossHub tool and The Cancer Genome Atlas (TCGA) transcriptomic data for 10 cancer types with at least 20 paired (tumor/normal) samples – breast, lung (AD and SCC), kidney (ccRCC and pRCC), thyroid, prostate, stomach, liver, and colon cancers. For qPCR analysis of gene expression, we used paired samples of non-small cell lung, breast, and colon cancers (40 for each). Results Using bioinformatics analysis, we identified a number of genes that were significantly upregulated in 10 cancer types and chose 5 poorly studied for further research: IQGAP3, KIF4A, KIF18B, NCAPH, and TROAP. The qPCR analysis in a cohort of Russian patients showed expression increase of all 5 genes in at least 80% of samples with a 4-fold median increase in colon cancer and more than a 10-fold median increase in breast and lung cancers. Next, with the CrossHub tool and TCGA data, we predicted that the most likely mechanism of upregulation of identified genes in lung, breast, and colon cancers is activation of E2F1, FOXM1, and MYBL transcription factors (TFs). Using qPCR, strong expression increase was shown for genes encoding these TFs and positive correlation was revealed between mRNA levels of 3 TFs and 5 identified genes (rs > 0.5 for all the pairs in 3 cancer types). Conclusions We revealed that IQGAP3, KIF4A, KIF18B, NCAPH, and TROAP genes are characterized by a drastic upregulation in 10 cancer types, including lung, breast, and colon cancers. These genes are potential “universal” oncogenes and possibly play a crucial role in carcinogenesis. The major mechanism of their upregulation is likely to be the activation by E2F1, FOXM1, and MYBL transcription factors. The revealed genes are potential therapeutic targets in multiple cancer types. Legal entity responsible for the study Alexey A. Dmitriev. Funding Russian Science Foundation (Grant 17-74-20064). Disclosure All authors have declared no conflicts of interest.