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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...

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Autores principales: Idaghdour, Youssef, Hodgkinson, Alan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5395977/
https://www.ncbi.nlm.nih.gov/pubmed/28420414
http://dx.doi.org/10.1186/s13073-017-0426-0
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author Idaghdour, Youssef
Hodgkinson, Alan
author_facet Idaghdour, Youssef
Hodgkinson, Alan
author_sort Idaghdour, Youssef
collection PubMed
description 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 × 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13073-017-0426-0) contains supplementary material, which is available to authorized users.
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spelling pubmed-53959772017-04-20 Integrated genomic analysis of mitochondrial RNA processing in human cancers Idaghdour, Youssef Hodgkinson, Alan Genome Med Research 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 × 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13073-017-0426-0) contains supplementary material, which is available to authorized users. BioMed Central 2017-04-18 /pmc/articles/PMC5395977/ /pubmed/28420414 http://dx.doi.org/10.1186/s13073-017-0426-0 Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Idaghdour, Youssef
Hodgkinson, Alan
Integrated genomic analysis of mitochondrial RNA processing in human cancers
title Integrated genomic analysis of mitochondrial RNA processing in human cancers
title_full Integrated genomic analysis of mitochondrial RNA processing in human cancers
title_fullStr Integrated genomic analysis of mitochondrial RNA processing in human cancers
title_full_unstemmed Integrated genomic analysis of mitochondrial RNA processing in human cancers
title_short Integrated genomic analysis of mitochondrial RNA processing in human cancers
title_sort integrated genomic analysis of mitochondrial rna processing in human cancers
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5395977/
https://www.ncbi.nlm.nih.gov/pubmed/28420414
http://dx.doi.org/10.1186/s13073-017-0426-0
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