title: Migration of mitochondrial DNA in the nuclear genome of colorectal adenocarcinoma.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama, 35294, USA.
authors.forename: Vinodh
authors.initials: V
authors.lastname: Srinivasainagendra
authors.affiliation: Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama, 35294, USA.|Present address: Department of Biological and Environmental Sciences, School of Natural Sciences and Mathematics, University of West Alabama, Livingston, Alabama, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Sandel
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, 35294, USA.
authors.forename: Bhupendra
authors.initials: B
authors.lastname: Singh
authors.affiliation: Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama, 35294, USA.
authors.forename: Aishwarya
authors.initials: A
authors.lastname: Sundaresan
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, 35294, USA.
authors.forename: Ved P
authors.initials: VP
authors.lastname: Mooga
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, 35294, USA.
authors.forename: Prachi
authors.initials: P
authors.lastname: Bajpai
authors.affiliation: Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama, 35294, USA. htiwari@uab.edu.
authors.forename: Hemant K
authors.initials: HK
authors.lastname: Tiwari
authors.affiliation: Departments of Genetics, Environmental Health, Center for Free Radical Biology, Center for Aging and UAB Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, 35294, USA. kksingh@uab.edu.|Departments of Pathology, Environmental Health, Center for Free Radical Biology, Center for Aging and UAB Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, 35294, USA. kksingh@uab.edu.|Birmingham Veterans Affairs Medical Center, Birmingham, Alabama, 35294, USA. kksingh@uab.edu.|Department of Genetics, School of Medicine, University of Alabama at Birmingham, Kaul Genetics Building, Suite 620, 720 20th St. South, Birmingham, AL, 35294, USA. kksingh@uab.edu.
authors.forename: Keshav K
authors.initials: KK
authors.lastname: Singh
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000230:Adenocarcinoma / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002467:Cell Nucleus / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D015179:Colorectal Neoplasms / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D004272:DNA, Mitochondrial; D004273:DNA, Neoplasm; D005260:Female; D016153:Genes, Suppressor; D016678:Genome; D015894:Genome, Human; D054629:Genome, Mitochondrial; D023281:Genomics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008666:Metalloendopeptidases / Q000235:genetics*; D008875:Middle Aged; D024101:Mitochondrial Proteins; D009154:Mutation; D012737:Sex Factors; D055815:Young Adult
chemical_list: D004272:DNA, Mitochondrial; D004273:DNA, Neoplasm; D024101:Mitochondrial Proteins; D008666:Metalloendopeptidases; C410807:YME1L1 protein, human; D000074183:ATPases Associated with Diverse Cellular Activities
keywords: Cancer; Colorectal cancer; Genetic instability; Mitochondria; Mitochondrial DNA; NUMT; Numtogenesis; Tumor; YME1L1; mtDNA transfer