Abstract
Cancer is a serious health problem with a high mortality rate worldwide. Given the relevance of mitochondria in numerous physiological and pathological mechanisms, such as adenosine triphosphate (ATP) synthesis, apoptosis, metabolism, cancer progression and drug resistance, mitochondrial genome (mtDNA) analysis has become of great interest in the study of human diseases, including cancer. To date, a high number of variants and mutations have been identified in different types of tumors, which coexist with normal alleles, a phenomenon named heteroplasmy. This mechanism is considered an intermediate state between the fixation or elimination of the acquired mutations. It is suggested that mutations, which confer adaptive advantages to tumor growth and invasion, are enriched in malignant cells. Notably, many recent studies have reported a heteroplasmy-shifting phenomenon as a potential shaper in tumor progression and treatment response, and we suggest that each cancer type also has a unique mitochondrial heteroplasmy-shifting profile. So far, a plethora of data evidencing correlations among heteroplasmy and cancer-related phenotypes are available, but still, not authentic demonstrations, and whether the heteroplasmy or the variation in mtDNA copy number (mtCNV) in cancer are cause or consequence remained unknown. Further studies are needed to support these findings and decipher their clinical implications and impact in the field of drug discovery aimed at treating human cancer.
Highlights
Despite the growing understanding of cancer biology and the constant effort to develop more effective diagnostic, follow-up and therapeutic strategies, these diseases still have important socio–economic implications worldwide [1]
Heteroplasmy can be higher if the mutated allele frequency (MAF) ranges from 20% to 95% or lower if the MAF ranges from 0.5% to
Even though evidence has shown that there is a mutational correlation between mitochondrial DNA (mtDNA) and nDNA, it is important to note that approximately 20% of patients have mutations in mitochondrial genes but not in nuclear genes, suggesting that some of these mtDNA mutations are potentially responsible for carcinogenic development [14], but no studies characterizing the role of these alterations in cancer have been carried out
Summary
Despite the growing understanding of cancer biology and the constant effort to develop more effective diagnostic, follow-up and therapeutic strategies, these diseases still have important socio–economic implications worldwide [1]. It has been shown that the mitochondrial DNA (mtDNA) of tumor cells accumulates many alterations, including punctual mutations, insertions, deletions and variations in mtDNA copy number (mtCNV), which trigger the metabolic reprogramming of transformed cells as a biological strategy that favors tumor cell proliferation and survival [7,8,9,10,11,12,13]. The critical threshold to observe a biochemical defect in the respiratory chain or for disease expression is undisclosed in cancer and scarcely analyzed in the studies that characterize the mtDNA variant landscape. This review focuses on describing the landscape of the heteroplasmy in cancer in order to contribute to the understanding of the biological processes involved, such as proliferation, metastasis and intratumoral heterogeneity, as well as heteroplasmy clinical implications
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