Asian-American variants of human papillomavirus type 16 have extensive mutations in theE2 gene and are highly amplified in cervical carcinomas

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Abstract
Human‐papillomavirus (HPV)‐E2 protein is involved in gene‐expression regulation 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 E1/E2 genes and high viral amplification are frequently found in HPV16‐positive carcinomas of some populations. In this study, we investigated whether retention of E1/E2 and viral amplification are associated with particular HPV16 E2 variants in cervical carcinomas. HPV16 detection, E1/E2 integrity and viral amplification were explored by Southern blot in 123 cervical carcinomas. 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 E1/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 were AA‐a and 5 AA‐c. Two E1/E2‐negative tumors also contained the AA‐c variant, while the remaining HPV16‐positive tumors contained only European variants. The E2 gene of AA variants showed 24 mutations, 19 identical in both sub‐classes. The 24 mutations were distributed throughout the entire gene and 19 result in 18 amino‐acid changes. The AA variants were associated with E1/E2‐positive carcinomas with more than 50 viral copies/cell (p = 0.035). The association of Asian‐American E2 variants with retention of E1/E2 suggests that E2 variation may be an alternative mechanism de‐regulating the expression of viral oncogenes. Int. J. Cancer 83:449–455, 1999.