Abstract
One of the challenges in the area of diagnostics of human thyroid cancer is a preoperative diagnosis of thyroid nodules with indeterminate cytology. Herein, we report an untargeted metabolomics analysis to identify circulating thyroid nodule metabolic signatures, to find new novel metabolic biomarkers. Untargeted gas chromatography-quadrupole-mass spectrometry was used to ascertain the specific plasma metabolic changes of thyroid nodule patients, which consisted of papillary thyroid carcinoma (PTC; n = 19), and multinodular goiter (MNG; n = 16), as compared to healthy subjects (n = 20). Diagnostic models were constructed using multivariate analyses such as principal component analysis, orthogonal partial least squares-discriminant analysis, and univariate analysis including One-way ANOVA and volcano plot by MetaboAnalyst and SIMCA software. Because of the multiple-testing issue, false discovery rate p-values were also computed for these functions. A total of 60 structurally annotated metabolites were subjected to statistical analysis. A combination of univariate and multivariate statistical analyses revealed a panel of metabolites responsible for the discrimination between thyroid nodules and healthy subjects, with variable importance in the projection (VIP) value greater than 0.8 and p-value less than 0.05. Significantly altered metabolites between thyroid nodules versus healthy persons are those associated with amino acids metabolism, the tricarboxylic acid cycle, fatty acids, and purine and pyrimidine metabolism, including cysteine, cystine, glutamic acid, α-ketoglutarate, 3-hydroxybutyric acid, adenosine-5-monophosphate, and uracil, respectively. Further, sucrose metabolism differed profoundly between thyroid nodule patients and healthy subjects. Moreover, according to the receiver operating characteristic (ROC) curve analysis, sucrose could discriminate PTC from MNG (area under ROC curve value = 0.92). This study enhanced our understanding of the distinct metabolic pathways associated with thyroid nodules, which enabled us to distinguish between patients and healthy subjects. In addition, our study showed extensive sucrose metabolism in the plasma of thyroid nodule patients, which provides a new metabolic signature of the thyroid nodule’s tumorigenesis. Accordingly, it suggests that sucrose can be considered as a circulating biomarker for differential diagnosis between malignancy and benignity in indeterminate thyroid nodules.
Highlights
Papillary thyroid cancer (PTC), which pathologically originates from thyroid follicular epithelial cells, has been globally documented as the most prevalent type of thyroid malignancy, among women (LiVolsi, 2011; Razavi et al, 2019)
The present study showed that the metabolism of about 11 amino acids, including (1) metabolites related to GSH biosynthesis, (2) methionine, (3) glycine, serine, and threonine, and (4) phenylalanine, had been changed in plasma of patients with thyroid nodules compared to healthy subjects
We performed an untargeted metabolomics investigation to improve our understanding of thyroid nodule metabolism, which could lead to finding novel early diagnostic biomarkers
Summary
Papillary thyroid cancer (PTC), which pathologically originates from thyroid follicular epithelial cells, has been globally documented as the most prevalent type of thyroid malignancy, among women (LiVolsi, 2011; Razavi et al, 2019). Ultrasound-guided fine-needle aspiration biopsy (FNAB) is the current preoperative method used for cytological evaluation of PTC and other thyroid nodules (Baloch et al, 2008). Despite its long-standing clinical success, FNAB possesses a major disadvantage: approximately 15–30% of thyroid FNABs cannot cytologically differentiate malignancy from benignity, the report would remain as “indeterminate thyroid lesions” (Bongiovanni et al, 2012). On account of this, according to the Bethesda system and a few more reports, the thyroid FNAB must be repeated in these cases to avoid false-positive or falsenegative results. The finding of novel noninvasive diagnostic biomarkers that enable practitioners to distinguish between benign and malignant nodules is a prerequisite to avoid FNAB repetition and unnecessary surgical procedures
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