Abstract
BackgroundThe highest rates of cervical cancer are found in developing countries. Frontline monitoring has reduced these rates in developed countries and present day screening programs primarily identify precancerous lesions termed cervical intraepithelial neoplasias (CIN). CIN lesions described as mild dysplasia (CIN I) are likely to spontaneously regress while CIN III lesions (severe dysplasia) are likely to progress if untreated. Thoughtful consideration of gene expression changes paralleling the progressive pre invasive neoplastic development will yield insight into the key casual events involved in cervical cancer development.ResultsIn this study, we have identified gene expression changes across 16 cervical cases (CIN I, CIN II, CIN III and normal cervical epithelium) using the unbiased long serial analysis of gene expression (L-SAGE) method. The 16 L-SAGE libraries were sequenced to the level of 2,481,387 tags, creating the largest SAGE data collection for cervical tissue worldwide. We have identified 222 genes differentially expressed between normal cervical tissue and CIN III. Many of these genes influence biological functions characteristic of cancer, such as cell death, cell growth/proliferation and cellular movement. Evaluation of these genes through network interactions identified multiple candidates that influence regulation of cellular transcription through chromatin remodelling (SMARCC1, NCOR1, MRFAP1 and MORF4L2). Further, these expression events are focused at the critical junction in disease development of moderate dysplasia (CIN II) indicating a role for chromatin remodelling as part of cervical cancer development.ConclusionWe have created a valuable publically available resource for the study of gene expression in precancerous cervical lesions. Our results indicate deregulation of the chromatin remodelling complex components and its influencing factors occur in the development of CIN lesions. The increase in SWI/SNF stabilizing molecule SMARCC1 and other novel genes has not been previously illustrated as events in the early stages of dysplasia development and thus not only provides novel candidate markers for screening but a biological function for targeting treatment.
Highlights
The highest rates of cervical cancer are found in developing countries
Events in expression change involving genes in Network A and Network B (DHFR, MORFL2, MRFAP1, nuclear receptor co-repressor 1 (NCOR1), and SMARCC1) occur at or before the stage of moderate dysplasia (CIN II). These events are maintained, at a reduced frequency, in cervical intraepithelial neoplasias (CIN) III suggesting a role in intermediate events prior to severe dysplasia that may be an important stepping stone in disease progression
(page number not for citation purposes) http://www.biomedcentral.com/1471-2164/9/64 rations in later stages may be due to the masking the of initial events by additional changes acquired in severe dysplasia [3,40,41]
Summary
The highest rates of cervical cancer are found in developing countries. Frontline monitoring has reduced these rates in developed countries and present day screening programs primarily identify precancerous lesions termed cervical intraepithelial neoplasias (CIN). CIN lesions described as mild dysplasia (CIN I) are likely to spontaneously regress while CIN III lesions (severe dysplasia) are likely to progress if untreated. Cervical cancer affects approximately 500,000 women worldwide each year with highest rates in developing countries [1]. Cervical intraepithelial neoplasia (CIN) is a precursor lesion to cervical cancer and can be further subdivided into CIN I, CIN II and CIN III (mild, moderate and severe dysplasia, respectively). Most CIN I lesions spontaneously regress to normal CIN III lesions are much more likely to progress to cervical cancer if left untreated [1]. Over 100 strains of HPV exist HPV 16 and HPV 18 are considered highly virulent strains and account for the majority of cervical cancers [1,2]
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