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Global Translational Medicine Telomere length, mtDNA copy number and colorectal cancer

LTL) was found to be inversely associated with mortality The heterogeneity of the results for studied biomarkers
from digestive cancer with OR = 1.53 (95% CI: 1.02 – 2.28) might be due to the variability across cancer sites, study
per 1 SD decrease in mtDNA-CN . Van Osch et al., in designs (retrospective or prospective studies with early
[45]
combined CRC cases from hospital series and Netherlands follow-up may reflect reverse causation), age and other
Cohort study, discovered lower mtDNA-CN in primary covariates impact, accuracy of LTL or mtDNA-CN
CRC tissue compared to a resected one as well as an measurement, and risk assessment for incident events or
[21]
inverse U-shaped relationship between CRC survival and cancer progression and mortality .
mtDNA-CN .
[46]
On the other hand, several studies have shown an 5. Limitations and strengths of the study
association between higher mtDNA-CN and risk of Our findings should be interpreted within the context of
incident CRC or CRC progression . In a meta-analysis, their potential limitations. First, we have to mention the
[48]
[47]
Mi et al. failed to find any association between mtDNA-CN modest sample size. Although our nested case-control
[49]
and several digestive system cancers (including CRC) . analysis involved the complete set of incident CRC cases
that developed in a large-scale cohort (9,360) within a
The mechanisms of the relationship between LTL and long-term follow-up period of 15 years, we ruled out only a
mtDNA-CN and CRC have not been fully understood. few CRC cases (because of the absence of DNA material or
A growing body of evidence has suggested the dual role insufficient quality of LTL and mtDNA-CN genotyping).
of telomeres (or telomere paradox) in carcinogenesis [39,50] . The controls satisfied strict exclusion criteria and were
Tumor cells with increased proliferation undergo faster frequency-matched to cases by age and sex. We believe that
attrition of telomeres than non-affected cells. Telomere this design likely covers a representative sample of incident
shortening works as a tumor-suppressing mechanism. CRC in this population.
On the other hand, for cell clones that escape the crisis,
critically short telomeres contribute to the mechanisms In addition, to ensure the completeness of registration,
related to telomere maintenance, including the reactivation we checked multiple sources of information for case
of telomerase, which stabilizes short telomeres , or rarer ascertainment (including the Cancer Register, Mortality
[50]
alternative telomere lengthening [45,51] , thus preventing cell Register, and repeated examinations of the cohort).
death and promoting tumor invasion. Critically short Another potential limitation might be related to the
telomeres also affect genomic aberrations and chromosome effect of cancer per se or cancer treatment on studied
[40]
instability, which, along with microsatellite instability , biomarkers ; thus, retrospective design or early follow-up
[57]
represent important pathways in the genesis of CRC . may reflect reverse causation. To avoid this shortage, we
[39]
The recently discovered telomere-driven chromothripsis used a prospective design and included only incident
(complex chromosomal rearrangement) is a widespread cancer cases. Besides that, we fulfilled two sensitivity
mutational phenomenon found in diverse tumor types . analyses with the exclusion of CRC cases that occurred
[51]
MtDNA-CN, as a proxy for mitochondria function, within the first 2 years or within the first 8 years after the
differs between cancer tissue and non-affected tissue for baseline blood was drawn, which did not substantially alter
a number of cancer types . The impact of mitochondria the results.
[45]
metabolism on tumor onset and progression is Another concern is the sex-dependent variance in LTL
heterogeneous by cancer type, and it has been shown to be and mtDNA-CN (due to the known higher values of both
related to CRC initiation [52,53] . Existing data have suggested biomarkers in women compared to men). To overcome
that mtDNA-CN changes depend on nuclear or mtDNA this potential limitation, we kept a similar sex distribution
mutations and serve as an adaptive response toward these among cases and controls (nearly 50%–60%), and the
mutations for certain cancer types [52,54] . A recent data have estimates were adjusted for sex. In addition, we obtained
supported the role of mtDNA mutations in metabolic ORs that were comparable to the combined dataset results
alterations (oxidative phosphorylation defects), facilitating after splitting the analysis by sex.
colon tumor , and suggested that somatic mutations in
[55]
mtDNA control region may be shaped by tumor-specific Taking into account the reported difference in the
[42,58]
selective pressure and involved in tumorigenesis . relationship between LTL and subtypes of CRC ,
[56]
Telomere attrition is involved in the regulation of we analyzed the risk of colon cancer and rectal cancer
mitochondrial genesis and function in the aging process, separately. This additional stratification did not materially
leading to their dysfunction and ROS formation; in affect the results.
particular, the role of telomere-p53-mitochondrial axis in Furthermore, our results are based on the investigation
cancer has been demonstrated . of a Caucasoid population in Novosibirsk (West Siberia),
[45]

Volume 2 Issue 1 (2023) 9 https://doi.org/10.36922/gtm.v2i1.184