Epi-drivers and cancer-testis genes

Wang et al. (1) reported new candidate cancer drivers by studying cancer-testis expression patterns in large cohorts of normal and cancer samples. The authors assumed that few cancer can be fully explained by the mutation drivers (mut-drivers) and thus they focused on studying epigenetic drivers (epi-drivers); genes that are altered by epigenetic mechanisms and confer selective growth advantage (2). The authors reasoned that since epi-drivers are aberrantly expressed in cancer due to underlying epigenetic alterations, it is possible to search for epi-drivers by using transcriptomics data. This is a very tempting idea since little is known about epi-drivers and their role in cancer is relatively poorly understood as compared to mut-drivers. However, epigenetics mechanisms alone do not fully explain altered gene expression, which can be caused by multiple factors such as mutations in promoter regions, DNA copy number alterations, mutations of the up-stream transcription factor or changes in signaling. For example in our recent transcriptome study of genes de-regulated and activated across multiple cancer types (3) we opted for not calling the broadly de-regulated genes as “epi-drivers”. Interestingly, Wang et al. regarded MEIOB (meiosis specific with OB domains) to be an epi-driver, while also noting that its expression is correlated with (and probably driven by) arm level and focal DNA copy number alterations (CNAs). While MEIOB is a reported cancer driver (4,5) that is differentially expressed in cancer, there is no epigenetic data to regard MEIOB as an epi-driver.