Abstract
BackgroundColorectal 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.MethodsWhole-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.ResultsOur 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.ConclusionsOur 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.
Highlights
Colorectal adenocarcinomas are characterized by abnormal mitochondrial DNA copy number and genomic instability, but a molecular interaction between mitochondrial and nuclear genome remains unknown
Downloaded data went through an intense quality control (QC) pipeline, which involved the use of (a) clinical information downloaded from The Cancer Genome Atlas (TCGA) Data Matrix, (b) short-reads alignment statistics derived from the Binary AlignMent (BAM) sequence data downloaded from Cancer Genomics Hub (CGHub), and (c) tagging and elimination of duplicate reads in the alignment data (BAM) using a popular next-generation sequencing tool, Picard 2.5
Adenocarcinoma genomes contain increased nuclear mtDNA (NUMT) compared to healthy genomes Since mitochondrial abnormalities are frequently described in cancer, we asked whether mitochondrial dysfunction results in increased prevalence of NUMTs in tumors
Summary
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. 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. Intact mitochondria containing mtDNA, mitochondrial RNA (mtRNA), and mitochondrial proteins are reported to localize into the nucleus [2,3,4,5,6,7,8,9] We have named this phenomenon of occurrence of nuclear mitochondria as numtogenesis. NUMT insertions are estimated to occur at a rate of ~5 × 10−6 per germ cell per generation [12]
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