The molecular genetics of cervical carcinoma

Abstract

In the pathogenesis of cervical carcinoma there are three major components, two of them related to the role of human papillomaviruses (HPV). First, the effect of viral E6 and E7 proteins. Second, the integration of viral DNA in chromosomal regions associated with well known tumour phenotypes. Some of these viral integrations occur recurrently at specific chromosomal locations, such as 8q24 and 12q15, both harbouring HPV18 and HPV16. And third, there are other recurrent genetic alterations not linked to HPV. Recurrent losses of heterozygosity (LOH) have been detected in chromosome regions 3p14–22, 4p16, 5p15, 6p21–22, 11q23, 17p13.3 without effect on p53, 18q12–22 and 19q13, all of them suggesting the alteration of putative tumour suppressor genes not yet identified. Recurrent amplification has been mapped to 3q+ arm, with the common region in 3q24–28 in 90% of invasive carcinomas. The mutator phenotype, microsatellite instability, plays a minor role and is detected in only 7% of cervical carcinomas. The development of cervical carcinoma requires the sequential occurrence and selection of several genetic alterations. The identification of the specific genes involved, and their correlation with specific tumour properties and stages could improve the understanding and perhaps the management of cervical carcinoma. © 1999 Cancer Research Campaign

Common fragile sites are preferential targets for HPV16 integrations in cervical tumors

“…Thus, the expression of cellular genes at or near the integration site may be affected. Clusters of HPV integration have been observed previously at 8q24 and 12q15 (Lazo, 1999). Multiple integrations into specific chromosomal loci may be indicative of genes that are common mutational targets in cervical carcinomas.…”

“…A generally random distribution is apparent. However, two chromosomal regions, 8q24 and 12q14-15, have been reported to be hot spots for HPV integration (Lazo, 1999). In this study, the chromosomal locations of 22 HPV16 integrations in cervical tumors have been determined.…”

Oncogenes and tumor angiogenesis: the HPV-16 E6 oncoprotein activates the vascular endothelial growth factor (VEGF) gene promoter in a p53 independent manner

“…However, other genetic alterations may contribute to the pathogenesis of cervical cancer (Lazo, 1999). In this regard, most of the HPV-associated dysplasias and cervical carcinomas also express high levels of the EGFR as well as EGFR ligands, such as TGF-a (Derynck et al, 1987;Ben-Bassat et al, 1997;Kersemaekers et al, 1999).…”

Inactivation of CHEK1 and EI24 is associated with the development of invasive cervical carcinoma: Clinical and prognostic implications

“…1,3 As HPV infections in most cases do not lead to cancer, and even a long latency period for the cancerous outcome in infected women suggests involvement of additional genetic alterations like functional inactivation of tumor suppressor genes (TSGs) or activation of oncogenes. 4 Investigations showing frequent chromosomal deletion in 11q23-q24 (20.4 Mb) in cervix, 5-7 breast, 8,9 lung, 10 colon 11 and ovarian 12 cancer and functional chromosome-transfer …”