Abstract
In the past decade, a high incidence of somatic mitochondrial DNA (mtDNA) mutations has been observed, mostly based on a fraction of the molecule, in various cancerous tissues; nevertheless, some of them were queried due to problems in data quality. Obviously, without a comprehensive understanding of mtDNA mutational profile in the cancerous tissue of a specific patient, it is unlikely to disclose the genuine relationship between somatic mtDNA mutations and tumorigenesis. To achieve this objective, the most straightforward way is to directly compare the whole mtDNA genome variation among three tissues (namely, cancerous tissue, para-cancerous tissue, and distant normal tissue) from the same patient. Considering the fact that most of the previous studies on the role of mtDNA in colorectal tumor focused merely on the D-loop or partial segment of the molecule, in the current study we have collected three tissues (cancerous, para-cancerous and normal tissues) respectively recruited from 20 patients with colorectal tumor and completely sequenced the mitochondrial genome of each tissue. Our results reveal a relatively lower incidence of somatic mutations in these patients; intriguingly, all somatic mutations are in heteroplasmic status. Surprisingly, the observed somatic mutations are not restricted to cancer tissues, for the para-cancer tissues and distant normal tissues also harbor somatic mtDNA mutations with a lower frequency than cancerous tissues but higher than that observed in the general population. Our results suggest that somatic mtDNA mutations in cancerous tissues could not be simply explained as a consequence of tumorigenesis; meanwhile, the somatic mtDNA mutations in normal tissues might reflect an altered physiological environment in cancer patients.
Highlights
In the past decade, the role of mitochondrial DNA mutation in tumorigenesis has received much attention
Most of the previous studies on the role of mitochondrial DNA (mtDNA) in colorectal tumor focused merely on the D-loop or partial segment of the molecule [28,29,30,31], only a few reports have focused on the mutational profile on its whole genome (Polyak et al 1998)
To get more insights into the relationship between mtDNA and colorectal tumor, in the current study we have recruited three tissues sampled from 20 patients with colorectal tumor; by sequencing the entire mtDNA genome from each tissue and comparing the mutational difference among three tissues from the same patient, our study revealed a relatively low mutational frequency and the heteroplasmic status of all the observed somatic mutations
Summary
The role of mitochondrial DNA (mtDNA) mutation in tumorigenesis has received much attention. Some studies suggested that the mtDNA somatic mutations likely result from the elevated reactive oxygen species (ROS) in tumor cell [3,4,5], because most of these mutations are T to C and G to A base transitions [1,2], similar to the mutation pattern of oxidative decay on DNA [6,7]. A recent study suggested that mtDNA mutations which produce the deficiency in respiratory complex I activity could contribute to tumor progression by enhancing the metastatic potential of tumor cells [12]. Further evidence is needed to elucidate the exact role that somatic mtDNA mutations have play in tumorigenesis
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