Papillomavirus integration sites as markers for cancer-relevant genes

Background Infection with specific types of human papillomavirus (HPVs) is causally related to genital, and head and neck tumors. However, for the induction of malignant progression additional genetic damages are required. One of these events is the direct disruption of the host genome by papillomavirus DNA integration. We tested whether it is possible to use HPV-DNA integration target sequences as markers for the localization of genes frequently affected in head and neck carcinomas. Methods. Standard cloning, sequencing, and hybridization methods, as well as cosmid-specific cDNA selection were utilized. HPV diagnosis was performed by PCR, and allele loss was determined by Southern blot analysis. Results. Sequences affected by HPV integration in a tonsillar carcinoma, and a sequence with similarities to HPV18-E5 were cloned and shown to map to chromosome 10q24 and 7p13-14 respectively. Both crones were located near chromosomal breakpoints and proto-oncogenes, and encode transcribed sequences. Three partial cDNAs derived from the 10q24 region could be isolated. Probes derived from the cloned sequences were useful in the detection of allele loss in 12 from 22 (54.5%) head and neck carcinomas. From these, 7 (31.8%) tested HPV positive. Conclusions. The results confirm that HPV integration regions show similar features in upper aerodigestive carcinomas and in cervical carcinomas. Furthermore, both locations analyzed contain cellular genes which are frequently altered in cancer cells, and therefore seem to be critical for normal cell growth.