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 Due to a lack of lethal cohort analyses, we provide additional unpublished data for metastatic disease.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).

Keywords: biomarkers; mitochondrial genome; mtDNA variation; prostate cancer.

Figure 1. Mitochondrial genome schematic representation and distribution of prostate tissue somatic mutations colored by gene complexes

(A) Double stranded circular mitochondrial genome depicting the distribution and Heavy (H, outside) or Light (L, inside) strand direction of transcription for 37 genes, 22 tRNAs and 2 rRNAs. (B) Distribution of somatic mutations among the OXPHOS complexes and non-coding regions of the mitochondrial genome with numbers below each bar indicating the number of mutations and patients defined by ethnicity, specifically, European (Eu), or African (AF), where whole mitochondrial genome, either by whole genome sequencing (WGS), whole mitochondrial genome sequencing (mWGS) or via amplicon derived capillary sequencing (cap), or coding region analyses, include whole exome sequencing (WES) was performed, which includes a total of eight studies to date. Tissue types include predominantly primary PCa, with smaller studies focused on benign prostate hyperplasia (BPH) or metastatic PCa, specifically bone metastases (BM) or soft tissue metastasis (STM). A single study included patient matched primary and metastatic tissue (*).

Figure 2. Number of somatic mtDNA variants correlated with clinical characteristics from four studies

(A) Sample combined Gleason score. (B) PSA level before radical prostatectomy or at diagnosis. (C) Age of patient at radical prostatectomy or diagnosis. The line and p-value represent the linear model for given characteristic by mutation number, generated using R with ggplot2 package [97, 98].