Analysis of mutations in the URR and E6/E7 oncogenes of HPV 16 cervical cancer isolates from central China.
High rates of cervical cancer have been reported from parts of China and this may reflect a predominance of cervical infection with particularly aggressive human papillomavirus (HPV) variants. This PCR-based investigation of cervical tumours from Sichuan province in central China demonstrated an HPV positivity rate of 88%. HPV 16 was most common (21/34, 61%), followed by HPV 18 (3/34, 9%), while types 33, 45, 58 and 59 were each identified in one specimen. Sequencing of up to 1349 bases of the 21 HPV 16-positive isolates, encompassing the enhancer/promoter of the upstream regulatory region (URR) and the E6 and E7 genes, revealed distinct patterns of genomic stability and variability. An overall mutation rate of 5% was seen in the URR. One isolate had a large deletion of 436 bases in the enhancer; while varying combinations of 21 point mutations were identified in the remainder, impacting several YY1, NF1, TEF-1 and Oct-1 sites. More sequence variations were found in E6 compared to E7 (81% vs. 52% of isolates showing at least one mutation), some of which resulted in changes to the translated amino acids. Since the E6/E7 genes encode the oncogenic proteins essential for malignant transformation, and as their expression is controlled by the URR, it is possible that some of the identified mutations altered the oncogenicity of the virus: either directly by changing amino acid sequences of the E6 or E7 oncoproteins, or indirectly through alterations to transcription factor binding sites in the URR.
Stephen
A L
AL
Department of Infectious Diseases, Faculty of Medicine, University of Sydney, Sydney, Australia.
Thompson
C H
CH
Tattersall
M H
MH
Cossart
Y E
YE
Rose
B R
BR
D002681:China / Q000453:epidemiology; D004279:DNA, Viral / Q000032:analysis; D005260:Female; D006801:Humans; D009154:Mutation; D009856:Oncogene Proteins, Viral / Q000235:genetics*; D016366:Open Reading Frames; D027383:Papillomaviridae / Q000235:genetics; D050725:Papillomavirus E7 Proteins; D015995:Prevalence; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D012097:Repressor Proteins; D002583:Uterine Cervical Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000821:virology
D004279:DNA, Viral; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16