Genomic integration of oncogenic HPV and gain of the human telomerase geneTERCat 3q26 are strongly associated events in the progression of uterine cervical dysplasia to invasive cancer


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Abstract

Recently proposed events associated with the progression of cervical intraepithelial neoplasia (CIN) 2/3 to cervical carcinoma include integration of human papillomavirus (HPV) into the host genome, genomic instability, and an increase in chromosome 3q copy number. In particular, the gene coding for the RNA component of telomerase (TERC) at 3q26 has been implicated as a possible candidate gene. Since it is not known to date how these events are temporally related during cervical carcinogenesis, the aim of the present study was to assess the correlation betweenTERCgene copy number and the physical status of HPV during progression in cervical neoplasia. Solitary precursor lesions of the uterine cervix (CIN 2/3,n= 17), lesions associated with a micro-invasive carcinoma (CIN 3&mCA,n= 13), and advanced invasive carcinomas (invCA,n= 7) were analysed by fluorescencein situhybridization (FISH) to determine the physical status of the virus andTERCgene copy number. TheTERCgene was increasingly gained with progression of CIN 2/3 (3 of 17) through CIN 3&mCA (7 of 13) to invCA (5 of 7). In the lesions exhibiting gain ofTERC, the virus was predominantly integrated. This was seen in eight of ten diploid lesions, indicating that these events can occur prior to aneuploidization and are strongly associated with the progression of CIN 3 to mCA and invCA (p< 0.001). With progression to carcinoma, a number of these lesions show polyploidization, resulting in aneuploidy and highTERCgene copy numbers. In conclusion, genomic integration of oncogenic HPV and gain of the human telomerase geneTERCappear to be important associated genetic events in the progression of uterine cervical dysplasia to invasive cancer.

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