The development of cervical cancer is highly associated with human papillomavirus (HPV) infection. Greater than 99% of all cervical tumors contain HPV DNA. Integration of high-risk HPV has been temporally associated with the acquisition of a malignant phenotype. Recent work from our lab has shown that HPV16, the most common high-risk HPV associated with cervical carcinoma, preferentially integrates at loci containing human common fragile sites (CFSs). CFSs are regions of genomic instability that have also been associated with deletions, translocations, and gene amplification during cancer development. The current work shows that HPV18, the second most prevalent highrisk HPV type found in cervical tumors, preferentially targets the CFSs. We identified 27 unique HPV18 integrations in cervical tumors, of which 63% (Po0.001) occur in CFSs. However, the distribution of HPV18 integrations found were profoundly different from those found for HPV16. Specifically, 30% of all HPV18 integrations occurred within the chromosomal band 8q24 near the c-myc proto-oncogene. None of the HPV16 integrations occurred in this region. Previous low-resolution mapping suggested that c-myc may be a target of HPV integration. Our data at nucleotide resolution confirm that in HPV18-positive cervical tumors, the region surrounding c-myc is indeed a hot spot of viral integration. These results demonstrate that CFSs are preferred sites of integration for HPV18 in cervical tumors. In addition, we have identified multiple cellular genes that have been disrupted by HPV18 integration in cervical tumors. Our results suggest that the sites of HPV18 integration are nonrandom and may play an important role in the development of cervical tumors.

Significantly elevated serum concentrations of lipid-associated sialic acid (LSA) were observed in 183 patients with invasive cervical carcinoma, 31 with uterine corpus adenocarcinoma and 71 with epithelial ovarian carcinoma prior to any treatment when compared with 50 normal control women (P < 0.05). Elevated LSA levels were also observed in five women with microinvasive cervical carcinoma and in four patients with uterine corpus leiomyosarcoma (P < 0.05). By contrast there were no significant elevations of serum LSA levels in 12 cases of cervical intraepithelial neoplasia, 32 of uterine corpus leiomyoma, 52 of benign ovarian cyst and 14 of mature ovarian teratoma when compared with normal control women. If the upper limit of the normal serum LSA concentration is set at 20 mg 100 ml-1, uterine corpus malignancy was distinguished from benign uterine corpus tumor with a sensitivity of 71% and a specificity of 94%; and ovarian malignancies were distinguished from benign ovarian masses with a sensitivity of 82% and a specificity of 85%. The positive predictive values of LSA assays in uterine and ovarian masses were 93% and 85%, respectively, whilst the negative predictive values were 75% and 81%, respectively. The sensitivity of LSA assays in cervical carcinoma was 57%. The present study suggests that serum LSA assays may be useful for the detection of gyncological malignancies.