Abstract
ObjectivesCervicovaginal fluid (CVF) can be considered as a potential source of biomarkers for diseases of the lower female reproductive tract. The fluid can easily be collected, thereby offering new opportunities such as the development of self tests. Our objective was to identify a CVF protein biomarker for cervical cancer or its precancerous state.MethodsA differential proteomics study was set up using CVF samples from healthy and precancerous women. Label-free spectral counting was applied to quantify protein abundances.ResultsThe proteome analysis revealed 16 candidate biomarkers of which alpha-actinin-4 (p = 0.001) and pyruvate kinase isozyme M1/M2 (p = 0.014) were most promising. Verification of alpha-actinin-4 by ELISA (n = 28) showed that this candidate biomarker discriminated between samples from healthy and both low-risk and high-risk HPV-infected women (p = 0.009). Additional analysis of longitudinal samples (n = 29) showed that alpha-actinin-4 levels correlated with virus persistence and clearing, with a discrimination of approximately 18 pg/ml.ConclusionsOur results show that CVF is an excellent source of protein biomarkers for detection of lower female genital tract pathologies and that alpha-actinin-4 derived from CVF is a promising candidate biomarker for the precancerous state of cervical cancer. Further studies regarding sensitivity and specificity of this biomarker will demonstrate its utility for improving current screening programs and/or its use for a cervical cancer self-diagnosis test.
Highlights
The human papillomavirus (HPV) is responsible for virtually all cervical cancers [1]
85% of all sexually active persons will be exposed to HPV, and the majority of all HR-HPV infections are virion producing suggesting that in addition to the viral genotype, several cofactors are closely associated with the persistence of the viral oncoproteins and the transformation of the cervical mucosa to malignant tissue [5,6]
We focus on the identification of candidate biomarkers for cervical neoplasia by comparing the protein composition of individual Cervicovaginal fluid (CVF) samples from healthy and precancerous (LSIL and HSIL) women
Summary
The human papillomavirus (HPV) is responsible for virtually all cervical cancers [1]. More than 150 variants of this virus exist, only certain genotypes, such as HPV 16, 18, 33, 45 and 58 are known as high-risk types (HR-HPV) [2]. Low-risk HPV types (LR-HPV), mainly HPV 6 and 11, seldom cause genital tumors; they do cause condylomata acuminata (anogenital warts) [3]. Persistent HPV oncoprotein expression (E6/E7) in HPV infected epithelial basal cells deregulates cell division [4]. Overexpression of these viral genes causes the deregulation of cell proliferation, metabolism, apoptosis, differentiation and genomic instability, all of which may lead to consecutive stages of cervical intra-epithelial neoplasia (CIN1, 2 and 3) or squamous intra-epithelial lesions (low-grade SIL and high-grade SIL). 85% of all sexually active persons will be exposed to HPV, and the majority of all HR-HPV infections are virion producing (which is limited in time) suggesting that in addition to the viral genotype, several cofactors are closely associated with the persistence of the viral oncoproteins and the transformation of the cervical mucosa to malignant tissue [5,6]
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