Integrated genomic analysis of mitochondrial RNA processing in human cancers

Background: The mitochondrial genome is transcribed as continuous polycistrons of RNA containing multiple genes. As a consequence, post-transcriptional events are critical for the regulation of gene expression and therefore all aspects of mitochondrial function. One particularly important process is the m(1)A/m(1)G RNA methylation of the ninth position of different mitochondrial tRNAs, which allows efficient processing of mitochondrial mRNAs and protein translation, and de-regulation of genes involved in these processes has been associated with altered mitochondrial function. Although mitochondria play a key role in cancer, the status of mitochondrial RNA processing in tumorigenesis is unknown. Methods: We measure and assess mitochondrial RNA processing using integrated genomic analysis of RNA sequencing and genotyping data from 1226 samples across 12 different cancer types. We focus on the levels of m(1)A and m(1)G RNA methylation in mitochondrial tRNAs in normal and tumor samples and use supervised and unsupervised statistical analysis to compare the levels of these modifications to patient whole genome genotypes, nuclear gene expression, and survival outcomes. Results: We find significant changes to m(1)A and m(1)G RNA methylation levels in mitochondrial tRNAs in tumor tissues across all cancers. Pathways of RNA processing are strongly associated with methylation levels in normal tissues (P = 3. 27 x 10(-31)), yet these associations are lost in tumors. Furthermore, we report 18 gene-by-disease-state interactions where altered RNA methylation levels occur under cancer status conditional on genotype, implicating genes associated with mitochondrial function or cancer (e.g., CACNA2D2, LMO2, and FLT3) and suggesting that nuclear genetic variation can potentially modulate an individual's ability to maintain unaltered rates of mitochondrial RNA processing under cancer status. Finally, we report a significant association between the magnitude of methylation level changes in tumors and patient survival outcomes. Conclusions: We report widespread variation of mitochondrial RNA processing between normal and tumor tissues across all cancer types investigated and show that these alterations are likely modulated by patient genotype and may impact patient survival outcomes. These results highlight the potential clinical relevance of altered mitochondrial RNA processing and provide broad new insights into the importance and complexity of these events in cancer.