Investigation of the urinary metabolic variations and the application in bladder cancer biomarker discovery

Abstract

Urine metabolomics have been used to identify biomarkers for clinical diseases. However, inter-individual variations and effect factors need to be further evaluated. In our study, we explored the urine metabolome in a cohort of 203 health adults, 6 patients with benign bladder lesions, and 53 patients with bladder cancer (BCa) using liquid chromatography coupled with high resolution mass spectrometry. Inter-individual analysis of both healthy controls and BCa patients showed that the urine metabolome was relatively stable. Further analysis indicated that sex and age affect inter-individual variations in urine metabolome. Metabolic pathways such as tryptophan metabolism, the citrate cycle, and pantothenate and CoA biosynthesis were found to be related to sex and age. To eliminate age and sex interference, additional BCa urine metabolomic biomarkers were explored using age and sex-matched urine samples (Test group: 44 health adults vs. 33 patients with BCa). Metabolic profiling of urine could significantly differentiate the cases with cancer from the controls and high-grade from low-grade BCa. A metabolite panel consisting of trans-2-dodecenoylcarnitine, serinyl-valine, feruloyl-2-hydroxyputrescine, and 3-hydroxynonanoyl carnitine were discovered to have good predictive ability for BCa with an area under the curve (AUC) of 0.956 (cross validation: AUC = 0.924). A panel of indolylacryloylglycine, N -galacturonyl-L-lysine, and aspartyl-glutamate was used to establish a robust model for high- and low-grade BCa distinction with AUC of 0.937 (cross validation: AUC = 0.891). External sample (26 control vs. 20 BCa) validation verified the acceptable accuracy of these models for BCa detection. Our study showed that urinary metabolomics is a useful strategy for differential analysis and biomarker discovery.

Characterization of LC-MS Based Urine Metabolomics in Healthy Subjects Across the Life Span

“…In the present study, we characterized the urine metabolomes of males and females in children and adults. Consistent with previous studies [4,6,7], amino acid metabolism, including tryptophan metabolism and arginine and proline metabolism, showed gender differences in both children and adults.…”

“…Most of the speci c gender-dependent metabolites in adults showed higher levels in males, including fatty acids, acylcarnitines, steroid hormones and dipeptides. Higher levels of acylcarnitines in males were found in our previous study, indicating a higher activity of fatty acid oxidation and energy production in males compared to females [7]. In addition, a higher level of steroid hormone biosynthesis was found in males, consistent with previous studies [17].…”

“…In 2018, we conducted a urine metabolomics study in 203 healthy adults to nd age-and gender-dependent urine metabolites. Metabolic pathways, such as tryptophan metabolism, citrate cycle, and pantothenate and CoA biosynthesis, were found to be related to gender and age [7]. Despite the large efforts in characterizing urine metabolomics in healthy subjects, most of the previous studies were focused on the confounding factors of the urine metabolome.…”

Profiling of polar urine metabolite extracts from Chinese colorectal cancer patients to screen for potential diagnostic and adverse-effect biomarkers

“…It has been qualified as a part of model of bladder cancer grading distinction. As the increase of pathologic stage malignant degree of gallbladder, the concentration of IAcrGly decreased in high-grade bladder cancer compared with low-grade bladder cancer 60 . Herein, a significant decrease of urinary concentration of IAcrGly in CRC patients was also found.…”

Plasma aromatase as a sensitive and selective potential biomarker of bladder cancer and its role in tumorigenesis

“…Females are diagnosed more frequently with a more progressive stage of the disease and display poorer treatment results after cystectomy and a higher risk of disease reoccurrence in comparison to males, a fact that may be explained by earlier invasion and progression. Moreover, it has been proven that estrogen, estrogen receptor, testosterone and dihydrotestosteron (34)(35)(36) as well as androgen receptor (37) are involved in BCa development. It has been reported that loss of androgen receptor expression was correlated with the progression of BCa stage (5).…”