Genetic Variability in the E6, E7, and L1 Genes of Human Papillomavirus Types 16 and 18 among Women in Saudi Arabia

Abstract

Cervical cancer is the eighth most frequent cancer in Saudi Arabia, and most cases are associated with human papillomavirus (HPV) types 16 and 18. HPV-induced carcinogenesis may be associated with the intra-type variant, genetic mutation, or the continuous expression of viral oncogenes E6 and E7. Infection efficiency and virus antigenicity may be affected by changes in the L1 gene. Thus, this retrospective cohort study analyzed E6, E7, and L1 gene mutations in cervical specimens collected from Saudi women positive for HPV16 or HPV18 infection. HPV16 and HPV18 lineages in these specimens were predominantly from Europe. The L83V mutation in the E6 gene of HPV16 showed sufficient oncogenic potential for progression to cervical cancer. By contrast, the L28F mutation in the E7 gene of HPV16 was associated with a low risk of cervical cancer. Other specific HPV16 and HPV18 mutations were associated with an increased risk of cancer, cancer progression, viral load, and age. Four novel mutations, K53T, K53N, R365P, and K443N, were identified in the L1 gene of HPV16. These findings for HPV16 and HPV18 lineages and mutations in the E6, E7, and L1 genes among women in Saudi Arabia may inform the design and development of effective molecular diagnostic tests and vaccination strategies for the Saudi population.

Keywords: E6 gene; E7 gene; HPV16; HPV18; L1 gene; cancer progression; cervical cancer; lineages; mutations; variants.

Figure 1

Schematic of the final study sample population after application of inclusion and exclusion criteria. Numerals in boxes represent the number of specimens. HKG indicates the housekeeping gene assay.

Figure 2

Novel mutations detected in the study population. (A) In specimen 219, A5796C led to changing lysine in position 53 to threonine (K53T). (B) In specimen 184, A5797C led to changing lysine in position 53 to asparagine (K53N). (C) In specimen 163, G6732C led to changing arginine in position 365 to proline (R365P). (D) In sample 136, A6967C led to changing lysine in position 443 to asparagine (K443N).

Figure 3

HPV16 phylogenetic trees. (A) Maximum likelihood analysis of the E6 nucleotide sequence. Specimens that did not cluster to any reference sequence were excluded. (B) Excluded specimens with complete L1 genes were reanalyzed by using maximum likelihood of the L1 nucleotide sequence. Numbers on the nodes indicate bootstrap values.

Figure 4

HPV18 phylogenetic tree. Maximum likelihood analysis of the E6 nucleotide sequence. Numbers on the nodes indicate bootstrap values. HSIL represents high-grade squamous intraepithelial lesion; SCC, squamous cell carcinoma.