Abstract
Cervical cancer remains one of the most prevalent cancers among females worldwide. Therefore, it is important to discover new biomarkers for early diagnosis of cervical intraepithelial neoplasia (CIN) and cervical cancer, preferably non-invasive ones. In the present study, we aimed to identify unique metabolic signatures for CINs and cervical cancers using global and targeted metabolomic profiling. Plasma samples (69 normal, 55 CIN1, 42 CIN2/3, and 60 cervical cancer) were examined by ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry (UPLC-QTOF-MS) coupled with multivariate statistical analysis. Metabolic pathways were analyzed using the integrated web-based tool MetaboAnalyst. A multivariate logistic regression analysis was conducted to evaluate the combined association of metabolites and human papillomavirus (HPV) status with the risk of cervical carcinogenesis. A total of 28 metabolites exhibiting discriminating levels among normal, CIN, and cervical cancer patients (Kruskal–Wallis test p < 0.05) were identified in the global profiling analysis. The pathway analysis showed significantly altered alanine, aspartate, and glutamate metabolic pathways (FDR p-value < 0.05) in both the discovery and validation phases. Seven metabolites (AMP, aspartate, glutamate, hypoxanthine, lactate, proline, and pyroglutamate) were discriminated between CINs and cervical cancer versus normal (area under the curve (AUC) value > 0.8). The levels of these metabolites were significantly high in patients versus normal (p < 0.0001) and were associated with increased risk of developing CIN2/3 and cervical cancer. Additionally, elevated levels of the seven metabolites combined with positive HPV status were correlated with substantial risk of cancer progression. These results demonstrated that metabolomics profiling is capable of distinguishing CINs and cervical cancers from normal and highlighted potential biomarkers for the early detection of cervical carcinogenesis.
Highlights
Cervical cancer is a common malignant disease in women around the world
These results demonstrated that metabolomics profiling is capable of distinguishing Cervical intraepithelial neoplasia (CIN) and cervical cancers from normal and highlighted potential biomarkers for the early detection of cervical carcinogenesis
The median ages calculated for the normal, CIN1, CIN2/3, and cervical cancer groups were 48, 35, 39.5, and 50 years, respectively
Summary
Cervical cancer is a common malignant disease in women around the world. It is the third most commonly diagnosed cancer (~485,000 cases) and the fourth leading cause of cancer-related deaths (236,000) per year worldwide [1,2]. Cervical intraepithelial neoplasia (CIN) 1–3 and carcinoma in situ are the precursor lesions of cervical cancer [3]. Other factors such as sexually transmitted infections, oral contraceptive use, smoking status, parity, and diet contribute to the development of cervical cancer [4]. Incidence decline can be attributed to regular application of Pap tests, which can reveal CINs and carcinoma in situ before they develop into cervical cancer, and vaccination [6]
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