Mitogenomic differences between the normal and tumor cells of colorectal cancer patients

Abstract

So far, a reliable spectrum of mitochondrial DNA mutations in colorectal cancer cells is still unknown, and neither is their significance in carcinogenesis. Indeed, it remains debatable whether mtDNA mutations are "drivers" or "passengers" of colorectal carcinogenesis. Thus, we analyzed 200 mitogenomes from normal and cancer tissues of 100 colorectal cancer patients. Minority variant mutations were detected at the 1% level. We showed that somatic mutations frequently occur in colorectal cancer cells (75%) and are randomly distributed across the mitochondrial genome. Mutational signatures of somatic mitogenome mutations suggest that they might arise through nucleotide deamination due to oxidative stress. The majority of somatic mutations localized within the coding region (in positions not known from the human phylogeny) and was potentially pathogenic to cell metabolism. Further analysis suggested that the relaxation of negative selection in the mitogenomes of colorectal cancer cells may allow accumulation of somatic mutations. Thus, a shift in glucose metabolism from oxidative phosphorylation to glycolysis may create advantageous conditions for accumulation of mtDNA mutations. Considering the fact that the presence of somatic mtDNA mutations was not associated with any clinicopathological features, we suggested that mtDNA somatic mutations are "passengers" rather than the cause of colorectal carcinogenesis.

TP53 somatic mutations are associated with somatic mitogenome substitutions but not indels in colorectal cancer cells

“…The mtDNA variability of normal and cancer samples investigated in the present study was previously described by Skonieczna et al . In brief, somatic mitogenome mutations were detected in 52 (approximately 78%) out of 67 CC patients .…”

“…Cancer and corresponding nontumour tissue specimens of individual patients were collected at the Department of Vascular Surgery and Angiology NCU CM in Bydgoszcz. Cancer specimens containing more than 80% cancer cells and normal colon tissues free from neoplastic cells were selected for the study after histopathological examination in the Department of Pathology NCU CM in Bydgoszcz, as performed in accordance with the methodology described in Skonieczna et al …”

“…The same DNA isolates used for TP53 amplification were previously used for mitogenome analysis. Mitochondrial genomes were sequenced with 454 sequencing technology and were reported in Skonieczna et al . In brief, mitogenomes were amplified in two PCR reactions as described by Fendt et al .…”

“…Hence, the only studies that can accurately delineate specific nucleotide changes introduced into CC cells during carcinogenesis are those in which normal colorectal tissues were used as matched samples to CC specimens. mtDNA analysis of such tissue comparison (cancer versus normal colorectal specimens) was applied in our previous study, in which we described mitogenome sequence variability in CC patients from the Polish population . In the present study, the same samples used for the above mentioned study were used to investigate the associations between TP53 gene variability and mitogenome mutagenesis in CC cells.…”

“…The human mitochondrial genome is highly mutated in colorectal cancer (CC) cells. Somatic substitutions, as well as insertions and deletions, are frequently observed in CC mitogenomes . Although somatic indels (mainly single nucleotide changes) occur predominantly in mononucleotide repeat regions, somatic substitutions target different mitochondrial (mtDNA) positions .…”