Mitochondrial genome variation and prostate cancer: a review of the mutational landscape and application to clinical management

Abstract

Prostate cancer is a genetic disease. While next generation sequencing has allowed for the emergence of molecular taxonomy, classification is restricted to the nuclear genome. Mutations within the maternally inherited mitochondrial genome are known to impact cancer pathogenesis, as a result of disturbances in energy metabolism and apoptosis. With a higher mutation rate, limited repair and increased copy number compared to the nuclear genome, the clinical relevance of mitochondrial DNA (mtDNA) variation requires deeper exploration. Here we provide a systematic review of the landscape of prostate cancer associated mtDNA variation. While the jury is still out on the association between inherited mtDNA variation and prostate cancer risk, we collate a total of 749 uniquely reported prostate cancer associated somatic mutations. Support exists for number of somatic events, extent of heteroplasmy, and rate of recurrence of mtDNA mutations, increasing with disease aggression. While, the predicted pathogenic impact for recurrent prostate cancer associated mutations appears negligible, evidence exists for carcinogenic mutations impacting the cytochrome c oxidase complex and regulating metastasis through elevated reactive oxygen species production. Due to a lack of lethal cohort analyses, we provide additional unpublished data for metastatic disease. Discussing the advantages of mtDNA as a prostate cancer biomarker, we provide a review of current progress of including elevated mtDNA levels, of a large somatic deletion, acquired tRNAs mutations, heteroplasmy and total number of somatic events (mutational load). We confirm via meta-analysis a significant association between mtDNA mutational load and pathological staging at diagnosis or surgery (p < 0.0001).

Reduced Levels of ATP Synthase Subunit ATP5F1A Correlate with Earlier‐Onset Prostate Cancer

“…As a consequence, combined OXPHOS complex deficiencies would be expected, as observed in 5 cases in our study. According to a recent review, 749 mtDNA mutations have been described for prostate cancer [ 34 ]. Only 80 of these were found in two or more patients, 15 of which are potentially pathogenic according to commonly used prediction tools [ 34 ].…”

“…According to a recent review, 749 mtDNA mutations have been described for prostate cancer [ 34 ]. Only 80 of these were found in two or more patients, 15 of which are potentially pathogenic according to commonly used prediction tools [ 34 ]. We are not aware of any previous study correlating nuclear OXPHOS subunit gene alterations to the frequency of OXPHOS deficiency in prostate carcinomas.…”

Cytochrome c Deficiency Confers Apoptosome and Mitochondrial Dysfunction in African-American Men with Prostate Cancer

“…AA prostate cancer is more aggressive, takes less time to relapse, shows molecular differences, and has greater likelihood of metastasis than CA prostate cancer (2)(3)(4)(5)(6)(7)(8). Although the molecular mechanisms driving acquisition of these characteristics in AA prostate cancer remain largely unknown, we and others have demonstrated that mitochondrial dysfunction is a key contributing factor to therapeutic resistance (9)(10)(11)(12). One of the reasons for greater prostate cancer aggressiveness in AA men is the existence of defective oxidative phosphorylation (OXPHOS) system in AA prostate cancer cells and tumors (9,12,13).…”

“…Although the molecular mechanisms driving acquisition of these characteristics in AA prostate cancer remain largely unknown, we and others have demonstrated that mitochondrial dysfunction is a key contributing factor to therapeutic resistance (9)(10)(11)(12). One of the reasons for greater prostate cancer aggressiveness in AA men is the existence of defective oxidative phosphorylation (OXPHOS) system in AA prostate cancer cells and tumors (9,12,13). We reported that mitochondrial DNA (mtDNA) copy number is reduced in nontumor prostatic tissues in AA men with prostate cancer compared with CA men with prostate cancer (11).…”

The Interplay of Tumor Stroma and Translational Factors in Endometrial Cancer

“…One possibility for how to overcome this dilemma and better characterize the cancerous lesions is mitochondrial DNA (mtDNA). Mitochondrial DNA (mtDNA) mutations are found in various cancer types [65][66][67][68]. Occurrences are found in every cell stage and a high number of copies are discovered in tumors, suggesting a less tight control and common mutations [69].…”