Thromboxane B2 br We also found di t butyl
We also found 2,6-di-t-butyl-4-hydroxymethylene-2,3,5,6-detetrahydrocyclohexanone to be elevated in PCa. This Thromboxane B2 is the tautomer of 3,5-di-t-butyl-4-hydroxybenzaldehyde (Figure 4C), a component of the qHTS assay used to identify small molecule agonists of the retinoid X nuclear receptor alpha (RXR) signaling pathway: Summary (AID 1159531).45 The nuclear expression of RXR alpha receptor subtype was reported to be generally downregulated in human PCa cell lines and specimens, and the loss or reduction of RXR alpha function is a critical determinant in prostate tumorigenesis.46 The high level of 2,6-di-t-butyl-4-hydroxymethylene-2,3,5,6-detetra-hydrocyclohexanone in PCa-positive urine samples may reveal the low utilization of all those types of agonist of RXR signaling pathway owing to the loss of RXR alpha function. Finally, the low level of estradiol in PCa-positive urine samples is consistent with previous studies identi-fying low circulation levels of estradiol as a PCa risk factor.47
There are several limitations associated with this study. Owing to the random nature of prostate biopsies, it is plausible that PCa-negative patients could be misclassified if they harbored disease missed on prostate biopsy. Secondly, the heterogeneous nature of PCa suggests that the urinary VOC PCa diagnostic model identified in this study will likely improve as sample size is increased and more patients from diverse backgrounds and environmental exposures are further assessed. Although this study focused on urinary VOCs, the role of non-VOC products of metabolism may also represent important biomarkers that should be accounted for as the final comprehensive PCa diagnostic model is developed. Finally, the impact of time of urine collection, diet, disease risk, personal genetic profile, and environmental exposures on VOC concentration measured is unknown but will be addressed in future studies.
In summary, the urinary VOC-based model shows promise as a noninvasive and reliable method for PCa diagnosis. The evaluation in an external cohort of patients demonstrated the high discrimi-nating power of this strategy in PCa diagnosis. The urinary VOC-based metabolite approach could likely be adapted into a clinically viable, highly sensitive, cost-effective portable diagnostic assay for PCa. The validity and effectiveness of those selected VOCs in PCa diagnosis need to be further confirmed in a larger cohort study. Although the investigation of the originating pathways of the VOCs
Qin Gao et al
Figure 4 Chemical Structures of 4 Representative VOCs Selected by the Regression Model (A-D)
Abbreviation: VOCs ¼ volatile organic compounds.
selected in the model is beyond the scope of this study, some VOCs linked to androgen receptor-modulated pathways were identified in our studies, suggesting a molecular rationale for the production of these VOCs related to PCa. The biological and chemical signifi-cance of these VOCs could be further studied to provide supporting information for the upstream proteomic pathways.
Clinical Practice Points
Owing to the low specificity of current PCa screening with serum PSA, up to 80% of men who are found to have elevated PSA value and subsequently undergo prostate biopsies will either not be diagnosed with PCa or be diagnosed with an indolent form of PCa, which is unlikely to cause significant morbidity or mortality. It is urgent to address the problem of overdiagnosis and overtreatment in PCa care.
We developed a urinary metabolite (ie, VOC)-based model to detect PCa with a higher accuracy (87%) than PSA alone (59%) in PCa screening, thus potentially providing a better alternative than the current PSA test to accurately and reliably diagnose PCa.
As a noninvasive and sensitive tool, the VOC model is ideally suited for early diagnosis of PCa. Future validation of our model will enable clinically relevant and cost-effective, point-of-care PCa screening and prognosis with the potential to save health care costs.
The authors thank the patients who consented to provide their clinical data and urine samples for this study. The Wiemer Family
Student Endowment for Excellence and Dodson Research Grant were provided for Q. Gao. The support by Dr. Keelung Hong Gift Fund for VOC Cancer Research Studies is also acknowledged. Heinric Williams was supported by the Mowad Endowment for New Discoveries fund. The authors also acknowledge Luisa F Castillo (University of Texas, El Paso) for her assistance in urine sample collection. L. Castillo was supported by the National Institute of General Medical Sciences of the National Institutes of Health under linked award numbers RL5GM118969, TL4GM118971, and UL1GM118970. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.