Asian-American variants of human papillomavirus type 16 have extensive mutations in the E2 gene and are highly amplified in cervical carcinomas

Human-papillomavirus (HPV)-E2 protein is involved in gene-expression regula tion and replication of HPV genome, Disruption of the E2 gene during viral integration has been proposed as a mechanism of tumoral progression, since the expression of E6/E7 viral oncogenes is allowed. However, retention of E 1/E2 genes and high viral amplification are frequently found in HPV16-posit ive carcinomas of some populations. In this study, we investigated whether retention of E1/E2 and viral amplification are associated with particular H PV16 E2 variants in cervical carcinomas, HPV16 detection, E1/E2 integrity a nd viral amplification were explored by Southern blot in 123 cervical carci nomas. HPV16 variants were identified by Southern blot and by sequencing E6 , L1/MY and E2 regions. Of 46 HPV16-positive tumors, 34 were positive for E 1/E2 and 14 of them showed a variant restriction pattern by mutations in E2 . All 14 were Asian-American (AA) variants and, of 11 sub-classified, 6 wer e AA-a and 5 AA-c, Two E1/E2-negative tumors also contained the AA-c varian t, while the remaining HPV16-positive tumors contained only European varian ts, The E2 gene of AA variants showed 24 mutations, 19 identical in both su b-classes. The 24 mutations were distributed throughout the entire gene and 19 result in 18 amino-acid changes. The AA variants were associated with E 1/E2-positive carcinomas with more than 50 viral copies/cell (p = 0.035). T he association of Asian-American E2 variants with retention of E1/E2 sugges ts that E2 variation may be an alternative mechanism de regulating the expr ession of viral oncogenes, Int, J, Cancer 83:449-455, 1999, (C) 1999 Wiley- Liss, Inc.