Hypermutation in the E2 gene of human papillomavirus type 16 in cervical intraepithelial neoplasia.
Persistent infection with oncogenic human papillomavirus (HPV) causes cervical cancer. However, viral genetic changes during cervical carcinogenesis are not fully understood. Recent studies have revealed the presence of adenine/thymine-clustered hypermutation in the long control region of the HPV16 genome in cervical intraepithelial neoplasia (CIN) lesions, and suggested that apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) proteins, which play a key role in innate immunity against retroviral infection, potentially introduce such hypermutation. This study reports for the first time the detection of adenine/thymine-clustered hypermutation in the E2 gene of HPV16 isolated from clinical specimens with low- and high-grade CIN lesions (CIN1/3). Differential DNA denaturation PCR, which utilizes lower denaturation temperatures to selectively amplify adenine/thymine-rich DNA, identified clusters of adenine/thymine mutations in the E2 gene in 4 of 11 CIN1 (36.4%), and 6 of 27 CIN3 (22.2%) samples. Interestingly, the number of mutations per sample was higher in CIN3 than in CIN1. Although the relevance of E2 hypermutation in cervical carcinogenesis remains unclear, the observed hypermutation patterns strongly imply involvement of APOBEC3 proteins in editing the HPV16 genome during natural viral infection.
Pathogen Genomics Center, National Institute of Infectious Diseases, Tokyo, Japan.
Iwao
I
Kukimoto
Pathogen Genomics Center, National Institute of Infectious Diseases, Tokyo, Japan.
Seiichiro
S
Mori
Department of Molecular Genetics, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
Satoru
S
Aoyama
Department of Molecular Genetics, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
Kousho
K
Wakae
Department of Molecular Genetics, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
Masamichi
M
Muramatsu
Department of Obstetrics and Gynecology, NTT Medical Center Tokyo, Tokyo, Japan.
Kazunari
K
Kondo
D000071478:APOBEC Deaminases; D000328:Adult; D000368:Aged; D003564:Cytidine Deaminase; D043525:Cytosine Deaminase / Q000235:genetics; D004279:DNA, Viral / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D016679:Genome, Viral; D052162:Human papillomavirus 16 / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D009856:Oncogene Proteins, Viral / Q000235:genetics*; D016133:Polymerase Chain Reaction; D002578:Uterine Cervical Dysplasia / Q000821:virology*
D004279:DNA, Viral; D004268:DNA-Binding Proteins; C054855:E2 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D043525:Cytosine Deaminase; D000071478:APOBEC Deaminases; C502889:APOBEC3 proteins, human; D003564:Cytidine Deaminase
APOBEC protein; cervical intraepithelial neoplasia; human papillomavirus; hypermutation