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. 2014 Apr;88(8):4514-21.
doi: 10.1128/JVI.03534-13. Epub 2014 Feb 5.

Human papillomavirus 45 genetic variation and cervical cancer risk worldwide

Alyce A Chen  1 , Daniëlle A M Heideman, Debby Boon, Tarik Gheit, Peter J F Snijders, Massimo Tommasino, Silvia Franceschi, Gary M Clifford; IARC HPV Variant Study Group
Collaborators, Affiliations

Human papillomavirus 45 genetic variation and cervical cancer risk worldwide

Alyce A Chen et al. J Virol. 2014 Apr.

Abstract

Human papillomavirus 45 (HPV45) is a member of the HPV18-related alpha-7 species and accounts for approximately 5% of all cervical cancer cases worldwide. This study evaluated the genetic diversity of HPV45 and the association of HPV45 variants with the risk of cervical cancer by sequencing the entire E6 and E7 open reading frames of 300 HPV45-positive cervical samples from 36 countries. A total of 43 HPV45 sequence variants were identified that formed 5 phylogenetic sublineages, A1, A2, A3, B1, and B2, the distribution of which varied by geographical region. Among 192 cases of cervical cancer and 101 controls, the B2 sublineage was significantly overrepresented in cervical cancer, both overall and in Africa and Europe separately. We show that the sequence analysis of E6 and E7 allows the classification of HPV45 variants and that the risk of cervical cancer may differ by HPV45 variant sublineage.

Importance: This work describes the largest study to date of human papillomavirus 45 (HPV45)-positive cervical samples and provides a comprehensive reference for phylogenetic classification for use in epidemiological studies of the carcinogenicity of HPV45 genetic variants, particularly as our findings suggest that the B2 sublineage of HPV45 is associated with a higher risk of cervical cancer.

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Figures

FIG 1
FIG 1
Phylogenetic tree of HPV45 variants based on E6 and E7. The numbers at the end of the branches correspond to the variant identifiers (IDs) listed in Table 2. The prototype sequence is variant 1 in sublineage A1.
FIG 2
FIG 2
Geographical distribution of HPV45 sublineages shown as a proportion of the total number of HPV45-positive samples collected from each region, irrespective of case-control status.
FIG 3
FIG 3
Positions of SNPs resulting in amino acid changes (red triangles) in HPV45 E6 and E7 open reading frames. Putative biologically relevant positions (green bars) based on sequence homology with HPV16 and HPV18 and E6* splicing sites (orange bars) are shown. CxxC is a zinc binding motif, RETQV is a PDZ binding motif, LxCxE is an RB1 binding motif, and SxxE is a casein kinase II recognition site. Y56 and I130 may be part of an LXXLL binding motif. Numbering of select amino acids is provided for reference.
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