Abstract
Regression of cervical intraepithelial neoplasia (CIN) 2-3 to CIN 1 or less is associated with immune response as demonstrated by immunohistochemistry in formaldehyde-fixed paraffin-embedded (FFPE) biopsies. Proteomic analysis of water-soluble proteins in supernatants of biopsy samples with LC-MS (LTQ-Orbitrap) was used to identify proteins predictive of CIN2-3 lesions regression. CIN2-3 in the biopsies and persistence (CIN2-3) or regression (≤CIN1) in follow-up cone biopsies was validated histologically by two experienced pathologists. In a learning set of 20 CIN2-3 (10 regressions and 10 persistence cases), supernatants were depleted of seven high abundance proteins prior to unidimensional LC-MS/MS protein analysis. Mean protein concentration was 0.81 mg/mL (range: 0.55–1.14). Multivariate statistical methods were used to identify proteins that were able to discriminate between regressive and persistent CIN2-3. The findings were validated in an independent test set of 20 CIN2-3 (10 regressions and 10 persistence cases). Multistep identification criteria identified 165 proteins. In the learning set, zinc finger protein 441 and phospholipase D6 independently discriminated between regressive and persistent CIN2-3 lesions and correctly classified all 20 patients. Nine regression and all persistence cases were correctly classified in the validation set. Zinc finger protein 441 and phospholipase D6 in supernatant samples detected by LTQ-Orbitrap can predict regression of CIN2-3.
Highlights
Among cancers affecting women, cervical cancer has the second highest occurrence worldwide, with an incidence in 2008 of 529,800 cases (14.5% in developed countries and 85.5% in developing countries) and 275,000 estimated deaths [1]
Regression of cervical intraepithelial neoplasia (CIN) 2-3 to CIN 1 or less is associated with immune response as demonstrated by immunohistochemistry in formaldehyde-fixed paraffin-embedded (FFPE) biopsies
Using three different statistical methods to analyse normalized spectral count data, this study has identified zinc finger protein 441 as a highly discriminating factor between CIN2-3 regressive and persistent lesions
Summary
Cervical cancer has the second highest occurrence worldwide, with an incidence in 2008 of 529,800 cases (14.5% in developed countries and 85.5% in developing countries) and 275,000 estimated deaths [1]. Noninvasive cervical intraepithelial neoplasia (CIN) precedes the development of invasive cancer and may progress from CIN2-3 to (micro)invasive cancer in 10–25 years on average [3]. A CIN lesion is, not a static event but a dynamic process that can persist and progress and spontaneously regress [4, 5]. 5–30% of all CIN2-3 lesions (confirmed by a histological punch biopsy) will develop invasive cancer [6]. Without cone excision, as many as 32–43% of CIN2-3 lesions will regress spontaneously [7]. In many countries including Norway, all punch biopsy-confirmed CIN2-3 lesions are usually treated with diathermic cone excision, a fairly aggressive therapy which can have serious adverse side effects [8]. The most serious late-complication is cervical insufficiency which can lead to late abortion and preterm delivery during the second and early third trimester of a future pregnancy [9, 10]
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