Correlates of Circulating Osteoprotegerin in Women with a Pathogenic or Likely Pathogenic Variant in the BRCA1 Gene.

BACKGROUND: Lower levels of osteoprotegerin (OPG), the decoy receptor for receptor activator of NFκB (RANK)-ligand, have been reported among women with a BRCA1 mutation, suggesting OPG may be marker of cancer risk. Whether various reproductive, hormonal, or lifestyle factors impact OPG levels in these women is unknown. METHODS: BRCA1 mutation carriers enrolled in a longitudinal study, no history of cancer, and a serum sample for OPG quantification, were included. Exposure information was collected through self-reported questionnaire at study enrollment and every 2 years thereafter. Serum OPG levels (pg/mL) were measured using an ELISA, and generalized linear models were used to assess the associations between reproductive, hormonal, and lifestyle exposures at the time of blood collection with serum OPG. Adjusted means were estimated using the fully adjusted model. RESULTS: A total of 701 women with a median age at blood collection of 39.0 years (18.0-82.0) were included. Older age (Spearman r = 0.24; P < 0.001) and current versus never smoking (98.82 vs. 86.24 pg/mL; Pcat < 0.001) were associated with significantly higher OPG, whereas ever versus never coffee consumption was associated with significantly lower OPG (85.92 vs. 94.05 pg/mL; Pcat = 0.03). There were no other significant associations for other exposures (P ≥ 0.06). The evaluated factors accounted for 7.5% of the variability in OPG. CONCLUSIONS: OPG is minimally influenced by hormonal and lifestyle factors among BRCA1 mutation carriers. IMPACT: These findings suggest that circulating OPG levels are not impacted by non-genetic factors in high-risk women.

Delineating the role of osteoprotegerin as a marker of breast cancer risk among women with a BRCA1 mutation.

Women with a pathogenic germline mutation in the BRCA1 gene face a very high lifetime risk of developing breast cancer, estimated at 72% by age 80. Prophylactic bilateral mastectomy is the only effective way to lower their risk; however, most women with a mutation opt for intensive screening with annual MRI and mammography. Given that the BRCA1 gene was identified over 20 years ago, there is a need to identify a novel non-surgical approach to hereditary breast cancer prevention. Here, we provide a review of the emerging preclinical and epidemiologic evidence implicating the dysregulation of progesterone-mediated receptor activator of nuclear factor κB (RANK) signaling in the pathogenesis of BRCA1-associated breast cancer. Experimental studies have demonstrated that RANK inhibition suppresses Brca1-mammary tumorigenesis, suggesting a potential target for prevention. Data from studies conducted among women with a BRCA1 mutation further support this pathway in BRCA1-associated breast cancer development. Progesterone-containing (but not estrogen-alone) hormone replacement therapy is associated with an increased risk of breast cancer in women with a BRCA1 mutation. Furthermore, BRCA1 mutation carriers have significantly lower levels of circulating osteoprotegerin (OPG), the decoy receptor for RANK-ligand (RANKL) and thus endogenous inhibitor of RANK signaling. OPG levels may be associated with the risk of disease, suggesting a role of this protein as a potential biomarker of breast cancer risk. This may improve upon current risk prediction models, stratifying women at the highest risk of developing the disease, and further identify those who may be targets for anti-RANKL chemoprevention. Collectively, the evidence supports therapeutic inhibition of the RANK pathway for the primary prevention of BRCA1-associated breast cancer, which may generate unique prevention strategies (without prophylactic surgery) and enhance quality of life.

Circulating cell-free mitochondrial DNA in brain health and disease: A systematic review and meta-analysis.

OBJECTIVES: Circulating cell-free mitochondrial DNA (ccf-mtDNA) are detectable fragments of mtDNA released from the cell as a result of mitochondrial dysfunction or apoptosis. The brain is one of the most energy demanding organs in the human body, and many neuropsychiatric and non-psychiatric neurological diseases have mitochondrial dysfunction associated with disease pathophysiology. Thus, we aimed to assess ccf-mtDNA as a potential biomarker for brain diseases. METHODS: We conducted a systematic review and meta-analyses of studies that examined peripheral and/or cerebrospinal fluid (CSF) ccf-mtDNA relevant to neuropsychiatric conditions, which we define as disorders of affect, behaviour and mood, and non-psychiatric neurological diseases, which consist of neurological diseases not related to psychiatry including neurodegenerative diseases. RESULTS: The results of the sensitivity analysis investigating the levels of peripheral ccf-mtDNA in neuropsychiatric studies showed no significant difference between cases and controls (Z = 1.57; p = 0.12), whereas the results of the sensitivity analysis investigating the levels of CSF ccf-mtDNA in non-psychiatric neurological diseases showed a decreasing trend in cases compared with controls (Z = 2.32; p = 0.02). Interestingly, the results indicate an overall mitochondrial stress associated mainly with non-psychiatric neurological diseases. CONCLUSIONS: Our study supports the involvement of mitochondrial stress, here defined as ccf-mtDNA, in brain diseases and encourage further investigation of ccf-mtDNA among patients with brain diseases.

Peripheral biomarkers of mitochondrial dysfunction in adolescents with bipolar disorder.

BACKGROUND: Mitochondrial dysfunction has been implicated in the pathophysiology of bipolar disorder (BD). Impediment of mitochondrial oxidative phosphorylation results in a shift toward anaerobic respiration and lactate production. Elevated CNS lactate levels in adults with BD inform the need to evaluate lactate in peripheral samples and early in the course of BD. Furthermore, there exists a recent surge of investigations looking at circulating cell-free mitochondrial DNA (ccf-mtDNA) as a potential biomarker as they are released from cells under physiological stress, apoptosis, or bioenergetic compromise. OBJECTIVES: To compare lactate and ccf-mtDNA, two different ways in assessing the mitochondrial health and function, in adolescents with BD versus healthy control adolescents (HC). METHODS: One-hundred and five adolescents (n = 64 BD, n = 41 HC) were included. Serum lactate level was measured using a commercially available colorimetric kit. Serum ccf-mtDNA concentration was measured using quantitative polymerase chain reaction from ccfDNA purified by commercially available spin columns. Diagnosis and mood symptoms were evaluated using semi-structured interviews. RESULTS: There is an increase in serum lactate level of adolescents with BD (1.319 ± 0.444 nmol/uL) versus HC (1.168 ± 0.353 nmol/uL; p = 0.043), but not ccf-mtDNA. Among BD adolescents, depression symptoms were negatively correlated with ccf-mtDNA levels (ρ = -0.289; p = 0.038) but loses significance when corrected for multiple comparison. Lactate was positively correlated with ccf-mtDNA in the overall sample (ρ = 0.201; p = 0.043). When examined by diagnosis, this association remained in BD (ρ = 0.273; p = 0.032), but not HC. CONCLUSION: These preliminary results indicate that elevated lactate is observed even among adolescents early in their course of BD, that the association between lactate and ccf-mtDNA appears to be specific to BD, and that ccf-mtDNA is potentially associated with depression symptoms in adolescent BD. In addition, the effect of psychotropic medications used in the treatment of BD on peripheral lactate and ccf-mtDNA requires further investigation.