Abstract
We investigated whether low mitochondrial DNA copy number (mtDNAcn) in peripheral blood leukocytes at diagnosis was associated with an increased risk of the aggressive form of the tumor and disease progression among localized prostate cancer (PCa) patients. We recruited 1,751 non-Hispanic white men with previously untreated PCa from The University of Texas MD Anderson Cancer Center. mtDNAcn was categorized into three groups according to tertiles. We used multivariate logistic regression to estimate the odds ratios (ORs) and 95 percent confidence intervals (95% CIs) for the association of mtDNAcn with the risk of having aggressive PCa at diagnosis. We used Cox proportional hazards model to estimate hazard ratios (HRs) and 95% CIs for disease progression. We observed an inverse association between aggressiveness of PCa and mtDNAcn (P < 0.001). In multivariate analysis, compared to patients in the highest tertile of mtDNAcn, those in the second and lowest tertiles had significantly increased risks of presenting with the high-risk form of PCa, as defined by the D'Amico criteria, with ORs of 1.33 (95% CI, 0.89-1.98; P = 0.17) and 1.53 (95% CI, 1.02-2.30; P = 0.04), respectively. Furthermore, PCa patients in the lowest and second tertiles combined relative to those in the highest tertile had a 56% increased risk of disease progression (HR, 1.56; 95% CI, 0.96-2.54; P = 0.07). In summary, our results suggested that low mtDNAcn in peripheral blood leukocytes was associated with aggressive PCa at diagnosis and might further predict poor progression-free survival among localized PCa patients.
Highlights
Mitochondria are key organelles that perform multiple central cellular functions such as energy production, cell proliferation, and apoptosis [1, 2]
We investigated whether low mitochondrial DNA copy number (mtDNAcn) in peripheral blood leukocytes was associated with aggressive features of prostate cancer (PCa) in a large cohort of patients with localized PCa
P for trend aAdjusted for age, BMI, smoking status and pack-year Abbreviations: mtDNAcn, mitochondrial DNA copy number; PCa, prostate cancer; odds ratios (ORs), odds ratio; CI, confidence interval and lowest tertiles combined had an increased risk of disease progression with a hazard ratios (HRs) of 1.59; after adjustment of age, BMI, smoking status, and pack-year, D’Amico risk groups, and treatments, the multivariate-adjusted HR was similar and borderline significant (HR, 1.56; 95 percent confidence intervals (95% CIs), 0.96–2.54; P = 0.07)
Summary
Mitochondria are key organelles that perform multiple central cellular functions such as energy production, cell proliferation, and apoptosis [1, 2]. Mitochondria are the only organelles in human cells that possess their own DNA (mtDNA). Each mitochondrion contains 1–15 mtDNA molecules [3, 4], and the number of mitochondria per cell ranges from several hundred to greater than 10, 000 mainly depending on the energy demand of the cell as well as environmental factors [5, 6]. Alterations in mtDNA including mutations and changes in copy number have been associated with multiple cancers including prostate cancer (PCa) [11,12,13,14,15,16,17,18]. When diagnosed at an early stage (i.e., localized or regional) the 5-year survival rate is almost 100%, but when the tumor has metastasized, the rate is only 28.0% [20]
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