Mitochondrial DNA Content as Risk Factor for Bladder Cancer and Its Association with Mitochondrial DNA Polymorphisms

Abstract

Mitochondrial DNA (mtDNA) content has been shown to be associated with cancer susceptibility. We identified 926 bladder cancer patients and compared these to 926 healthy-controls frequency matched on age, gender, and ethnicity. Patients diagnosed with bladder cancer had significantly decreased mtDNA content when compared to control subjects (median: 0.98 vs. 1.04, p<0.001). Low mtDNA content (ie, less than the median in control subjects) was associated with a statistically significant increased risk of bladder cancer, when compared with high mtDNA content (Odds Ratio (OR) = 1.37, 95% CI = 1.13 to 1.66, p<0.001). In a trend analysis, a statistically significant dose–response relationship was detected between lower mtDNA content and increasing risk of bladder cancer (P for trend <0.001). When stratified by host characteristics, advanced age (>65 years), male/female sex and positive smoking history were all significantly associated with low mtDNA content and increased risk of bladder cancer. We identified two unique mtDNA polymorphisms significantly associated with risk of bladder cancer: mitot10464c (OR=1.39 95%CI: 1.00–1.93, p=0.048) and mitoa4918g (OR=1.40, 95% CI: 1.00–1.95, p=0.049). Analysis of the joint effect of low mtDNA content and unfavorable mtDNA polymorphisms revealed a 2.5 fold increased risk of bladder cancer (OR=2.50, 95% CI: 1.60–3.94, p<0.001). Significant interaction was observed between mitoa4918g and mtDNA content (p for interaction = 0.028). Low mtDNA content was associated with increased risk of bladder cancer and we identified new susceptibility mtDNA alleles associated with increased risk that require further investigation into the biological underpinnings of bladder carcinogenesis.

Oncogenic Potential of CYP24A1 in Lung Adenocarcinoma

“…Additionally, mitochondrial DNA content has been positively correlated with risk for various cancer risks, including lung and bladder cancers. 24,25 So far among various molecular regulators, RAS-p66 Shcmediated signaling has been linked to mitochondrial DNA replication 26 and proper mitochondrial division reported to be a requisite for the mutant RAS protein (KRAS G12D )-mediated transformation. 27 Thus, our findings on the linkage between RAS and CYP24A1 and an impact on mitochondrial DNA content are unique, and future studies will improve our molecular understanding of this process.…”

Altered mitochondrial DNA copy number contributes to human cancer risk: evidence from an updated meta-analysis

“…Our analysis included 36 studies that focused on diverse cancer types from different origins around the world 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 . To reduce the uncertainty induced by confusing factors in the meta-analysis, we evaluated the association between mtDNA content with cancer risk in an overall analysis, as well as stratified analyses by cancer types, genders, ages, ethnicity and life styles.…”

The Genomic Origins of Small Mitochondrial RNAs: Are They Transcribed by the Mitochondrial DNA or by Mitochondrial Pseudogenes within the Nucleus (NUMTs)?

“…In contrast, if transcribed by the mtDNA, then we predict the abundance of these small RNAs will be higher in tissues that are rich in mitochondria relative to tissues that are poor in mitochondrial content. In particular, tissues that exhibit naturally enriched levels of mitochondria, such as the cancerous cells, would be predicted to show increased abundances of small mitochondrial RNAs when compared with their healthy counterparts that have less mitochondria (Williams et al. 2015; Vyas et al.…”