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Mitogenome germline mutations and colorectal cancer risk in Polish population.

ABSTRACT: Introduction:To date, several nuclear DNA variants have been shown to be associated with increased risk of developing colorectal cancer. Despite the fact that mitochondria play an important role in carcinogenesis, little is known about inherited mitochondrial DNA mutations that could be involved in this disease. Thus, potential associations between inherited mutations in the entire mitochondrial genomes and colorectal cancer were analysed in this study. Material and methods:Two hundred mitogenome sequences determined for colorectal cancer patients and healthy individuals from Poland were used to investigate the association between mtDNA alleles or haplogroups and colorectal cancer. Additional mtDNA control region haplotypes determined for 1353 individuals from the general Polish population were used for comparison of haplogroup and certain allele frequencies between case and control groups. Results:The non-R clades together with their diagnostic T alleles at positions 12705 and 16223 were observed with higher frequencies in healthy individuals than in colorectal cancer patients. Nevertheless, the differences of the R macrohaplogroup (as well as 12705 or 16223 alleles) frequencies between cases and controls were statistically insignificant after Bonferroni correction. Most of the non-R clades were of Asian and African origin, but none of them were prevalent in the control group. Moreover, neither mtDNA alleles nor haplogroups were associated with clinicopathological parameters of colorectal cancer patients. Conclusions:Contrary to some previous reports, the findings of this study do not support the hypothesis that mitochondrial DNA variants contribute to inherited predisposition to colorectal cancer.

SUBMITTER: Skonieczna K

PROVIDER: S-EPMC7069428 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Mitogenome germline mutations and colorectal cancer risk in Polish population.

Skonieczna Katarzyna K Jawień Arkadiusz A Marszałek Andrzej A Grzybowski Tomasz T

Archives of medical science : AMS 20190116 2

<h4>Introduction</h4>To date, several nuclear DNA variants have been shown to be associated with increased risk of developing colorectal cancer. Despite the fact that mitochondria play an important role in carcinogenesis, little is known about inherited mitochondrial DNA mutations that could be involved in this disease. Thus, potential associations between inherited mutations in the entire mitochondrial genomes and colorectal cancer were analysed in this study.<h4>Material and methods</h4>Two hu ...[more]

PMID: 32190148

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Project description:Familial adenomatous polyposis (FAP) is an inherited syndrome caused by a heterozygous adenomatous polyposis coli (APC) germline mutation, associated with a profound lifetime risk for colorectal cancer. While it is well accepted that tumorigenic transformation is initiated following acquisition of a second mutation and loss of function of the APC gene, the role of heterozygous APC mutation in this process is yet to be discovered. This work aimed to explore whether a heterozygous APC mutation induces molecular defects underlying tumorigenic transformation and how different APC germline mutations predict disease severity. Three FAP-human embryonic stem cell lines (FAP1/2/3-hESC lines) carrying germline mutations at different locations of the APC gene, and two control hESC lines free of the APC mutation, were differentiated into colon organoids and analyzed by immunohistochemistry and RNA sequencing. In addition, data regarding the genotype and clinical phenotype of the embryo donor parents were collected from medical records. FAP-hESCs carrying a complete loss-of-function of a single APC allele (FAP3) generated complex and molecularly mature colon organoids, which were similar to controls. In contrast, FAP-hESCs carrying APC truncation mutations (FAP1 and FAP2) generated only few cyst-like structures and cell aggregates of various shape, occasionally with luminal parts, which aligned with their failure to upregulate critical differentiation genes early in the process, as shown by RNA sequencing. Abnormal disease phenotype was shown also in non-pathological colon of FAP patients by the randomly distribution of proliferating cells throughout the crypts, compared to their focused localization in the lower part of the crypt in healthy/non-FAP patients. Genotype/phenotype analysis revealed correlations between the colon organoid maturation potential and FAP severity in the carrier parents. In conclusion, this study suggest that a single truncated APC allele is sufficient to initiate early molecular tumorigenic activity. In addition, the results hint that patient-specific hESC-derived colon organoids can probably predict disease severity among FAP patients.

Dataset Information

Mitogenome germline mutations and colorectal cancer risk in Polish population.

Publications

Mitogenome germline mutations and colorectal cancer risk in Polish population.

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