ASSOCIATION OF HUMAN PAPILLOMAVIRUS TYPE-16 INTEGRATION IN THE E2 GENE WITH POOR DISEASE-FREE SURVIVAL FROM CERVICAL-CANCER

To determine the clinical relevance of human papillomavirus (HPV) inte gration and E2 function suggested by in vitro studies, we investigated 50 patients with HPV 16 positive primary cervical carcinoma (stage Ib -IV) diagnosed and treated at one institution. The physical state of H PV was determined by colorimetric in situ hybridization and was not fo und to vary by stage. Overall, 62% of tumors had integrated HPV, 16% h ad episomal and 22% had both integrated and episomal. The E11E2 region was evaluated by 8 separate polymerase chain reactions, which resulte d in overlapping products. There was no significant variation in abili ty to amplify the E1/E2 region with stage. E1/E2 amplification correla ted with physical state. Nearly all tumors with episomal or mixed HPV 16 DNA amplified all 8 E1/E2 fragments. Half of the tumors with integr ated HPV 16 DNA failed to amplify one or more E1/E2 fragments. Disrupt ions were most frequent in the E2 region. For all 46 patients receivin g curative therapy, the Kaplan-Meier estimate of disease-free survival was determined for those whose primary tumors had amplifiable E2 comp ared with those lacking one or more E2 DNA fragments. Disruption of E2 was associated with significantly shortened disease-free survival. (C ) 1997 Wiley-Liss, Inc,.