title: Asian-american variants of human papillomavirus type 16 have extensive mutations in the E2 gene and are highly amplified in cervical carcinomas.
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.
authors.affiliation: Multidisciplinary Research Laboratory, Military School of Medical Graduates and Army School of Medicine, University of the Army and Air Force, Mexico City, Mexico.
authors.forename: L
authors.initials: L
authors.lastname: Casas
authors.forename: S C
authors.initials: SC
authors.lastname: Galvan
authors.forename: R M
authors.initials: RM
authors.lastname: Ordoñez
authors.forename: N
authors.initials: N
authors.lastname: Lopez
authors.forename: M
authors.initials: M
authors.lastname: Guido
authors.forename: J
authors.initials: J
authors.lastname: Berumen
mesh_terms: D019943:Amino Acid Substitution; D001213:Asian; D015139:Blotting, Southern; D036022:Capsid Proteins; D004252:DNA Mutational Analysis; D004279:DNA, Viral / Q000235:genetics; D004268:DNA-Binding Proteins; D005260:Female; D018628:Gene Dosage; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000235:genetics*; D027383:Papillomaviridae / Q000235:genetics* / Q000302:isolation & purification; D030361:Papillomavirus Infections / Q000208:ethnology / Q000235:genetics*; D017354:Point Mutation / Q000235:genetics; D012097:Repressor Proteins; D014412:Tumor Virus Infections / Q000208:ethnology / Q000235:genetics*; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000821:virology*
chemical_list: D036022:Capsid Proteins; D004279:DNA, Viral; D004268:DNA-Binding Proteins; C054855:E2 protein, Human papillomavirus type 16; C068651:E6 protein, Human papillomavirus type 16; C114580:HPV L1 protein, Human papillomavirus; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins