Mitochondrial microsatellite instability in patients with metastatic colorectal cancer

Venderbosch, Sabine; Vliet, Shannon van; Craenmehr, M.H.C.; Simmer, Femke; Haan, A.F.J. de; Punt, C. J. A.; Koopman, Miriam; Nagtegaal, Irıs D.

doi:10.1007/s00428-015-1733-8

Cited by 9 publications

(18 citation statements)

References 44 publications

(99 reference statements)

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“…Less data are available for metastatic CRC. The detection rate of mitochondrial instability for the LN of this study was in accordance with a recent publication on metastatic CRC 23 considering all three investigated loci (54.4%) or D16184 only (1.6%), negligibly lower than reported by these authors for D310 only (50.5%) and little higher than reported in the case of D514 only (4.9%). In contrast, the rate of mtMSI in DM of our patient cohort was less than half of that reported by others.…”

Section: Discussionsupporting

confidence: 92%

Mitochondrial DNA alteration in primary and metastatic colorectal cancer: Different frequency and association with selected clinicopathological and molecular markers

Kleist

Meurer²,

Poetsch³

2017

Tumour Biol.

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This study attempts to determine whether primary tumor tissue could reliably represent metastatic colorectal cancer in therapy-guiding analysis of mitochondrial microsatellite instability. Therefore, we investigated the concordance of microsatellite instability in D310, D514, and D16184 (mitochondrial DNA displacement loop), and its association with selected clinical categories and KRAS/NRAS/BRAF/PIK3CA/TP53 mutation status between primary and metastatic colorectal cancer tissue from 119 patients. Displacement loop microsatellite instability was significantly more frequently seen in lymph node metastases (53.1%) compared to primary tumors (37.5%) and distant metastases (21.4%) (p = 0.0183 and p = 0.0005). The discordant rate was significantly higher in lymph node metastases/primary tumor pairs (74.6%) than in distant metastases/primary tumor pairs (52.4%) or lymph node metastases/distant metastases pairs (51.6%) (p = 0.0113 and p = 0.0261) with more gain (86.7%) than loss (61.1%) of microsatellite instability in the discordant lymph node metastases (p = 0.0024). Displacement loop instability occurred significantly more frequently in lymph node metastases and distant metastases of patients with early colorectal cancer onset age <60 years (p = 0.0122 and p = 0.0129), was found with a significant high rate in a small cohort of TP53-mutated distant metastases (p = 0.0418), and was associated with TP53 wild-type status of primary tumors (p = 0.0009), but did not correlate with KRAS, NRAS, BRAF, or PIK3CA mutations. In conclusion, mitochondrial microsatellite instability and its association with selected clinical and molecular markers are discordant in primary and metastatic colorectal cancer, which could have importance for surveillance and therapeutic strategies.

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Section: Discussionsupporting

confidence: 92%

Mitochondrial DNA alteration in primary and metastatic colorectal cancer: Different frequency and association with selected clinicopathological and molecular markers

Kleist

Meurer²,

Poetsch³

2017

Tumour Biol.

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“…Regarding mtDNA, microsatellite instability (mainly in D310 region) was found in 40% of colorectal cancer patients analyzed here. Nevertheless, the occurrence of such mutations may not have the same molecular background as the nuclear ones, as previous studies have shown lack of any association between the occurrence of mitochondrial and nuclear microsatellite instability (Venderbosch et al., ). It was previously proposed that polymerase gamma may be involved in mitochondrial length variation in D310 sequence in cancer (Skonieczna et al., ), but such associations were not observed for colorectal cancer patients (Linkowska et al., ).…”

Section: Discussionmentioning

confidence: 94%

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

et al. 2018

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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.

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“…To the best of our knowledge, no association has been identified between mtDNA mutations and mtMSI status, and no mtMSI-positive GC cases have exhibited large deletions in mtDNA (44). Furthermore, mtMSI appears to be particularly frequent at the D310 locus; however, the high prevalence of mtMSI was not associated with the prognosis of patients with CRC (23,47). Notably, a previous study reported that stromal mtMSI may have possibly served an independent role in the pathogenesis of CC (48).…”

Section: Gastric Cancer Colon Cancer Rectum Cancermentioning

confidence: 83%

“…Mitochondrial MSI (mtMSI) in GIC. mtMSI has been reported to frequently occur in GC and CRC (23,24). In the present study, the mtMSI in 69 Chinese patients with GIC were analyzed.…”

Section: Homoplasmic Mutations Of the Mtdna D-loop In Gicmentioning

confidence: 95%

Mitochondrial DNA D‑loop lesions with the enhancement of DNA repair contribute to gastrointestinal cancer progression

et al. 2018

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Gastrointestinal cancer (GIC) is a worldwide public health problem with a high mortality rate. Mitochondrial DNA (mtDNA) mutations in the displacement loop (D-loop) region are quite common in various types of primary human cancers; however, their role in the pathogenesis of GIC is controversial. In the present study, tumor and para-tumor tissues were selected from 18 patients with gastric cancer (GC), 21 patients with colon cancer (CC) and 30 patients with rectal cancer (RC). The mtDNA D-loop was analyzed by sequencing and reverse transcription-quantitative polymerase chain reaction. Furthermore, DNA oxidative damage and DNA repair functioning were detected by immunohistochemistry. The results demonstrated that increased mtDNA deletion was not evident in GIC; however, significant DNA oxidative damage was significant in RC by detecting 8-hydroxyguanine expression. In addition, over-activated DNA repair was identified in CC and RC through the detection of 8-oxo-20-deoxyguanosine glycosylase 1 expression. The mtDNA D-loop had a specific mutation hotspot region, and the level of mtDNA D-loop mutations was correlated with the progression of the GIC.The mutations of the mtDNA D-loop were primarily homoplasmic in GIC and often transitioned at pyrimidine sites. Mitochondrial microsatellite instability, including the formation of poly-cytidine stretches, was common in GIC. These results demonstrate the occurrence of mtDNA D-loop mutations in GIC in Chinese patients and support the correlation of these mutations with carcinoma progression. Over-activated DNA repair function possibly repairs the GIC mtDNA lesions.

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Mitochondrial microsatellite instability in patients with metastatic colorectal cancer

Cited by 9 publications

References 44 publications

Mitochondrial DNA alteration in primary and metastatic colorectal cancer: Different frequency and association with selected clinicopathological and molecular markers

Mitochondrial DNA alteration in primary and metastatic colorectal cancer: Different frequency and association with selected clinicopathological and molecular markers

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

Mitochondrial DNA D‑loop lesions with the enhancement of DNA repair contribute to gastrointestinal cancer progression

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