Somatic Mutations throughout the Entire Mitochondrial Genome Are Associated with Elevated PSA Levels in Prostate Cancer Patients

Abstract

The genetic etiology of prostate cancer, the most common form of male cancer in western countries, is complex and the interplay of disease genes with environmental factors is far from being understood. Studies on somatic mitochondrial DNA (mtDNA) mutations have become an important aspect of cancer research because these mutations might have functional consequences and/or might serve as biosensors for tumor detection and progression. We sequenced the entire mitochondrial genome (16,569 bp) from 30 prospectively collected pairs of macrodissected cancerous and benign cells from prostate cancer patients and compared their genetic variability. Given recent concerns regarding the authenticity of newly discovered mtDNA mutations, we implemented a high-quality procedure for mtDNA whole-genome sequencing. In addition, the mitochondrial genes MT-CO2, MT-CO3, MT-ATP6, and MT-ND6 were sequenced in further 35 paired samples from prostate cancer patients. We identified a total of 41 somatic mutations in 22 out of 30 patients: the majority of these mutations have not previously been observed in the human phylogeny. The presence of somatic mutations in transfer RNAs (tRNAs) was found to be associated with elevated PSA levels (14.25 ± 5.44 versus 7.15 ± 4.32 ng/ml; p = 0.004). The level and degree of heteroplasmy increased with increasing tumor activity. In summary, somatic mutations in the mitochondrial genome are frequent events in prostate cancer. Mutations mapping to mitochondrial tRNAs, ribosomal RNAs, and protein coding genes might impair processes that occur within the mitochondrial compartment (e.g., transcription, RNA processing, and translation) and might finally affect oxidative phosphorylation.

Mutational load of the mitochondrial genome predicts pathological features and biochemical recurrence in prostate cancer

“…When correcting for length, we found a greater, though not significant, frequency of variation within the non-protein coding than protein coding regions ( p = 0.013 by two-sided Fischer's exact test) (Figure 1B). This proved to be significant for the D-loop and the tRNA regions ( p = 0.0044 by two-sided Fischer's exact test), as previously reported [16]. Of the 41 SNVs mapping to protein coding regions, 26 directly alter an amino acid (non-synonymous mutation) of which 21 have biological potential defined by termination of translation (n=2) or by PolyPhen-2 computational prediction as either possibly (n=2) or probably damaging (n=17).…”

“…Including 50 variants in the mtDNA variation database MITOMAP, as at 9 th of April 2016, a total of 380 prostate cancer associated somatic mtDNA mutations have been reported [16,20–23]. Most recently, McCrow et al, 2016 highlighted that prostate cancer presentation is more likely characterized by the total accumulation of mtDNA mutations rather than specific mtDNA mutations [22], while Ju et al, 2014, looking at mtDNA mutations across a range of cancer tissue types, suggested that functionally deleterious mtDNA mutations were more likely to be heteroplasmic as a result of negative selection [20].…”

Mitochondrial DNA mutations in human tumor cells

“…Certain researchers have suggested that the mtDNA mutations in tumor cells acted as a stimulus to tumors and contributed to tumorigenesis and tumor progression (12,15,16,31,32). The following evidence supports this theory.…”

Mitochondrial Haplogroups and Polymorphisms Reveal No Association with Sporadic Prostate Cancer in a Southern European Population

“…Somatic mutations in mitochondrial DNA (mtDNA) have been identified in various tumors, including breast cancer [48], squamous cell carcinoma [49], and prostate cancer [15], [50]. In squamous cell carcinoma, they were associated with better survival.…”