Allele-specific expression is selected in tumorigenesis, results from epigenetic changes and has prognostic relevance

Allele-specific expression (ASE) is the differential abundance in levels of mRNAs that originated from the paternal and maternal copies of a gene. Such allelic imbalances can contribute to phenotypic variation and influence disease traits, including cancer. There is common ASE in tumors that results from somatic copy-number alterations (CNAs) at the DNA level, but there also exist other causes of ASE: cis-acting genetic or epigenetic variation that can lead to differential expression between the two alleles. However, the latter, non-CNA mechanisms of ASE remain understudied in cancer, as well as their role in tumor evolution and impact on clinical outcomes. By integrating a wide variety of genomic and transcriptomic pan-cancer data from the TCGA project, we show that ASE favoring the preferential expression of the mutant allele in some driver genes is subject to positive selection, and that these events are associated with worse overall survival across all cancer types. We found that the impact of ASE triggered by non-CNA causes is substantial, and we propose that some instances of cis-ASE are explained by the epigenetic changes affecting alleles differently. Furthermore, as a second mechanism, we find that splicing-altering mutations are selected in various cancer genes and result in ASE. We anticipate that the study and understanding of the role of mutant allele imbalances at the mRNA level can help understand epigenetic changes during cancer evolution, as well as identify new prognostic markers and therapeutic approaches that target altered allelic expression in tumors.