Migration of mitochondrial DNA in the nuclear genome of colorectal adenocarcinoma

Genome Medicine

Aishwarya Sundaresan¹  Hemant K. Tiwari¹  Michael W. Sandel¹  Vinodh Srinivasainagendra¹  Ved P. Mooga²  Prachi Bajpai²  Bhupendra Singh²  Keshav K. Singh³ 

[1] Department of Biostatistics, School of Public Health, University of Alabama at Birmingham;Department of Genetics, University of Alabama at Birmingham;Departments of Genetics, Environmental Health, Center for Free Radical Biology, Center for Aging and UAB Comprehensive Cancer Center, University of Alabama at Birmingham;

关键词: Cancer;    Tumor;    Colorectal cancer;    Mitochondria;    Mitochondrial DNA;    YME1L1;   

DOI  :  10.1186/s13073-017-0420-6

来源: DOAJ

【 摘 要 】

Abstract Background Colorectal adenocarcinomas are characterized by abnormal mitochondrial DNA (mtDNA) copy number and genomic instability, but a molecular interaction between mitochondrial and nuclear genome remains unknown. Here we report the discovery of increased copies of nuclear mtDNA (NUMT) in colorectal adenocarcinomas, which supports link between mtDNA and genomic instability in the nucleus. We name this phenomenon of nuclear occurrence of mitochondrial component as numtogenesis. We provide a description of NUMT abundance and distribution in tumor versus matched blood-derived normal genomes. Methods Whole-genome sequence data were obtained for colon adenocarcinoma and rectum adenocarcinoma patients participating in The Cancer Genome Atlas, via the Cancer Genomics Hub, using the GeneTorrent file acquisition tool. Data were analyzed to determine NUMT proportion and distribution on a genome-wide scale. A NUMT suppressor gene was identified by comparing numtogenesis in other organisms. Results Our study reveals that colorectal adenocarcinoma genomes, on average, contains up to 4.2-fold more somatic NUMTs than matched normal genomes. Women colorectal tumors contained more NUMT than men. NUMT abundance in tumor predicted parallel abundance in blood. NUMT abundance positively correlated with GC content and gene density. Increased numtogenesis was observed with higher mortality. We identified YME1L1, a human homolog of yeast YME1 (yeast mitochondrial DNA escape 1) to be frequently mutated in colorectal tumors. YME1L1 was also mutated in tumors derived from other tissues. We show that inactivation of YME1L1 results in increased transfer of mtDNA in the nuclear genome. Conclusions Our study demonstrates increased somatic transfer of mtDNA in colorectal tumors. Our study also reveals sex-based differences in frequency of NUMT occurrence and that NUMT in blood reflects NUMT in tumors, suggesting NUMT may be used as a biomarker for tumorigenesis. We identify YME1L1 as the first NUMT suppressor gene in human and demonstrate that inactivation of YME1L1 induces migration of mtDNA to the nuclear genome. Our study reveals that numtogenesis plays an important role in the development of cancer.

【 授权许可】

Unknown