Abstract

INTRODUCTION AND OBJECTIVE: Our group identified multiple small open reading frames (ORFs) in the mitochondrial genome. These ORFs produce small mitochondrial-derived peptides (MDPs) that are measurable in plasma including humanin, small humanin-like peptide-2 (SHLP2), and mitochondrial open reading frame of the 12S rRNA (MOTSc). Previously we found that higher serum SHLP2 was linked with lower prostate cancer (PC) risk in white men, but no significant association was observed in black men. We tested whether SHLP2 and other MDPs as measured in plasma correlated with PC risk by race in a separate sample of men undergoing prostate biopsy. METHODS: Plasma SHLP2, humanin, and MOTSc were measured by ELISA in 198 men (50/49 white/black cases; 50/49 white/black controls) undergoing prostate biopsy at the Durham Veterans Affair hospital. Logistic and multinomial regression models were used to test the association between each MDP and PC diagnosis and low-grade (grade group 1) and high-grade PC (grade group 2-5). Models were adjusted for age, body mass index, digital rectal examination, and PSA. We tested the interaction between MDPs and race in predicting PC. RESULTS: There was a statistically significant p-interaction between all 3 MDPs and race for predicting PC (all p-interaction≤0.01). Among white men, higher values of all MDPs were significantly associated with lower PC diagnosis (all p≤0.001). In contrast, in black men, all MDPs were unrelated to PC diagnosis. Similarly, higher expression of all MDPs was associated with decreased risk of both low- and high-grade PC in white men (all p≤0.005) but none were associated with low- or high-grade in black men. Black controls had lower MOTSc (p=0.026) and SHLP2 (p=0.001) values than white controls. CONCLUSIONS: Higher expression of all three MDPs studied (plasma SHLP2, humanin, and MOTSc) were associated with lower PC risk in white men but not in black men. However, in general, black controls had lower MDP levels than white controls. These data support the importance of MDPs and perhaps mitochondrial dysfunction in PC and suggest greater dysfunction in black men (lower MDP levels in controls), which may contribute to excess PC risk in black men, though this requires confirmation in future larger studies. Source of Funding: Supported by DODW81XWH, K24CA160653, and U54CA233465

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