Amplification of human papillomavirus types 16 and 18 in invasive cervical cancer

The distribution and amplification patterns of human papillomavirus were studied in 15 human papillomavirus (HPV) 16- and six HPV18-positive cervical carcinomas by colorimetric in situ hybridization (ISH). The findings were correlated with the viral copy number and status of E1/E2 viral genes in the tumor DNA, as studied by dot blot analysis and the polymerase chain reaction, respectively. The tumors were classified according to the ISH signal into single dot, multidot, diffuse, and mixed patterns. The signal was homogeneously distributed only in single dot tumors and was clearly heterogeneous in tumors with mixed nuclear signal patterns, including both dot and diffuse signals. The single dot pattern predominated in HPV 18-positive tumors (83%), whereas the multidot pattern was most frequent in HPV 16-positive tumors (47%). Diffuse and mixed patterns were noted only in HPV 16-positive tumors (33%). The lowest mean copy of number per cell was observed in single dot tumors (25 +/- 15) with an ascendent trend toward the diffuse signal tumors (2832 +/- 2281). E1/E2 genes were disrupted in 75% of the single/multidot tumors and in none of the diffuse/mixed tumors. These data suggest diffuse signals originate by episomal amplification and dot signals originate by viral integration. Diffuse and dot patterns suggest different mechanisms of viral transformation.