Multimodal deregulation of imprinted gene HM13 : a pan-cancer study

HM13, an imprinted gene that is frequently overexpressed in cancer, has been repeatedly associated with tumor progression and lower survival. We have previously demonstrated that loss of imprinting (LOI) and copy number gains (CNG) were independently associated with HM13 overexpression in breast cancer. As HM13 contains MCTS2, a retrogene copy of the MCTS1 oncogene, we conducted a pan-cancer study (TCGA) of HM13 to evaluate the causes of its deregulation and how this impacts MCTS2 expression. We found recurrent LOI and CNG to be independently associated with HM13 (including MCTS2) overexpression. Additionally, DNA methylation aberrations, intronic retention, and aberrant splicing of HM13 were found to be common in LOI and CNG samples, as well as in cancers featuring specific intronic mutations, whereas this was far less the case for other cancer samples and controls. By relying on breast cancer single molecule RNA-seq data, aberrant transcripts were found to frequently contain MCTS2 open reading frames. Given MCTS2’s previous pseudogene status, MCTS2 expression was further validated by evaluating riboseq and mass spectrometry data and by the observation of higher homology with the original MCTS1 oncogene at the protein than at the cDNA level. Finally, extreme MCTS2 overexpression was clinically linked to the TNBC molecular signature in breast cancer and to lower survival rates in kidney, colon and lung cancer. Our results demonstrate frequent HM13 deregulation pan-cancer through multiple mechanisms, and subsequent isoform switching with MCTS2 – a novel putative oncogene – mediating at least part of the impact.