Molecular mechanisms in cervical carcinogenesis : Studies of clonality, somatic genetic alterations and human papillomavirus variants in cervical pre-invasive and invasive cancer

Abstract: Cervical cancer derives from a series of pre-invasive cervical neoplastic lesions termed CIN I-III (Cervical Intraepithelial Neoplasia) via typical multiple-step processes. In contrast to premalignant disorders in other organs, different degrees of CIN possess a distinct biological behaviour where a proportion spontaneously regress or persist, whereas some progress to invasive cancer. A meticulous examination of pathological, genetical and viological aspects of the mechanisms for this dynamic event was performed.Clonality and clonal lineages of CIN and invasive cancer were studied on microdissected single or multiple synchronous lesions. Independent CIN lesions were both monoclonal and polyclonal, whereas invasive cancer and adjacent CIN inevitably were monoclonal in origin. Mostly when multiple lesions were analyzed, the invasive cancer shared an identical clonality pattern with the co-existing CIN but one third of multiple CIN lesions were multifocal and their clonal origin was not identical to synchronous invasive cancer. The data suggest that CIN lesions vary in their biological behaviour although they are morphologically similar. Polyclonal CIN may represent a benign proliferation,whereas monoclonal CIN more likely progresses to an invasive stage. Multifocal origin of CIN suggests that multiple cells from the cervix undergo transformation simultaneously, implying an essential role of a "field defect" (HPV?) in cervical carcinogenesis.Genetic deletions (LOH) of chromosome 3p, 6p and 6q were investigated in CIN and SCC. The detection of allelic losses and the deletion mapping suggested that the alterations of 3p22-21.3, 3p21.1, HLA region on 6p and 6q16.1-21 were frequent and early genetic events in cervical cancer and imply that these chromosome regions harbour potential tumor suppressor genes important in thecervical carcinogenesis.HPV 16 E6 and L1 gene variations were analyzed in CIN lesions independent or synchronous with invasive cancer. Distribution of HPV in the infected cervix is more restricted to neoplastic lesions than normal epithelia. Identical HPV types and variants were detected in multiple synchronous CIN and invasive cancer, emphasizing the role of persistence of the same oncogenic HPV in the initiation of transformation events. The most common HPV 16 E6 and L1 gene variations were established. The data provide a base for further in vitro studies and for design of vaccine strategy for prevention of HPV 16 associated diseases.