Urinary Metabotyping of Bladder Cancer Using Two-Dimensional
Gas Chromatography Time-of-Flight Mass Spectrometry
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Abstract
Cystoscopy
is the gold standard clinical diagnosis of human bladder
cancer (BC). As cystoscopy is expensive and invasive, it compromises
patients’ compliance toward surveillance screening and challenges
the detection of recurrent BC. Therefore, the development of a noninvasive
method for the diagnosis and surveillance of BC and the elucidation
of BC progression become pertinent. In this study, urine samples from
38 BC patients and 61 non-BC controls were subjected to urinary metabotyping
using two-dimensional gas chromatography time-of-flight mass spectrometry
(GC×GC–TOFMS). Subsequent to data preprocessing and chemometric
analysis, the orthogonal partial least-squares discriminant analysis
(OPLS-DA, R<sup>2</sup>X = 0.278, R<sup>2</sup>Y = 0.904 and Q<sup>2</sup>Y (cumulative) = 0.398) model was validated using permutation
tests and receiver operating characteristic (ROC) analysis. Marker
metabolites were further screened from the OPLS-DA model using statistical
tests. GC×GC–TOFMS urinary metabotyping demonstrated 100%
specificity and 71% sensitivity in detecting BC, while 100% specificity
and 46% sensitivity were observed via cytology. In addition, the model
revealed 46 metabolites that characterize human BC. Among the perturbed
metabolic pathways, our clinical finding on the alteration of the
tryptophan-quinolinic metabolic axis in BC suggested the potential
roles of kynurenine in the malignancy and therapy of BC. In conclusion,
global urinary metabotyping holds potential for the noninvasive diagnosis
and surveillance of BC in clinics. In addition, perturbed metabolic
pathways gleaned from urinary metabotyping shed new and established
insights on the biology of human BC