Abstract 2107: Clonal patterns of chromosomal aberrations in cervical cancers and precursor lesions

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Abstract CGH analysis of cervical carcinomas has shown a non-random pattern of chromosomal aberrations with 3q gain being present in the vast majority of these tumors. Gains of genetic material on 1q, 5p, 8q and 20q, and losses on 2q, 3p and 11q, were also frequently detected. We developed a nine-probe FISH assay targeting these regions with the goal to investigate the dynamics of clonal evolution of cervical precancerous and cancerous lesions. BAC clone contigs for five oncogenes, COX2 on 1q, TERC on 3q, TERT on 5p, MYC on 8q, and ZNF217 on 20q, and three tumor suppressor genes, ING5 on 2p, FHIT on 3p and CHEK1 on 11q were assembled and labeled by nick-translation. Centromere 7 was included as a control probe for the ploidy of the cell. Objectives: •Determine gain and loss patterns of the targeted genes within cervical intraepithelial neoplasia (CIN) and invasive cervical carcinomas (ICC) •Characterize clonal patterns in CIN lesions and invasive cervical carcinomas with the goal to understand clonal evolution during cervical carcinogenesis Tissue specimens (CIN and ICC) were obtained from the Gynecological Department, Karolinska University Hospital, Sweden, and the University Hospital Mannheim, Germany. 50 µm paraffin sections were marked for the representative lesions by a pathologist, microdissected and disintegrated into single cell suspensions. One cytospin slide for each lesion was hybridized subsequently with three FISH probe panels containing three probes each. Using a relocation software allowed determining signal patterns of all nine probes for each of the nuclei evaluated. These data were then translated into gain/loss patterns by an enumerator program developed at NCBI. We plan to analyze 20 ICC, 20 CIN3 lesions and 20 CIN1 lesions. To date, we have completed the analysis of two cancer specimens and three severely dysplastic lesions (CIN3). All five lesions showed distinct clonal cell populations characterized by specific signal patterns with a TERC gain (3q) being the only aberration present in all of the clones. Both cancers and one CIN3 lesion consisted mainly of diploid cell populations in which the TERC gain was accompanied by a loss of FHIT (3p) suggestive of an isochromosome 3q as the major chromosomal aberration event. The other two CIN3 lesions consisted mainly of tetraploid cell populations with a TERC gain but no concomitant FHIT loss. In three of the lesions only two or three changes were observed: 1) FHIT loss and TERC gain, 2) FHIT loss, TERC gain and CHEK1 loss, and 3) TERC gain and COX2 gain. The other two lesions showed clonal changes involving five to seven of the markers. We expect that the findings from this study will improve our understanding of clonal development during cervical carcinogenesis and with that our understanding of genome dynamics in early carcinogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2107. doi:1538-7445.AM2012-2107