Distribution of human papillomavirus 58 and 52 E6/E7 variants in cervical neoplasia in Chinese women

doi:10.1016/j.ygyno.2010.08.032

Gynecologic Oncology

Volume 119, Issue 3, December 2010, Pages 436-443

https://doi.org/10.1016/j.ygyno.2010.08.032 Get rights and content

Abstract

Objectives

The specific intratype HPV genome variations may be associated with the development of cervical cancer in specific geographic regions and a given population. Human papillomavirus (HPV) 58 and 52 have been found to be relatively prevalent among Asian women including Chinese women. This study aimed to assess the risk of HPV 58 and 52 variants for cervical cancer and its precursors in Chinese women.

Methods

A total of 2021cervical samples were collected. After DNA extraction and genotyping, a total of 298 (177 HPV58-single positive and 121 HPV52-single positive) DNA samples were analyzed for E6 and E7 sequence variations by direct sequencing.

Results

A total of 29 new reported variations of HPV 58 and 52 were found. For HPV58, the presence of C632T (T20I) and G760A (G63S) variants in E7 showed a positive trend of the association with the severity of neoplasia (P_trend < 0.05, χ² test for trend).

Conclusions

These findings suggest that C632T (T20I) and G760A (G63S) variants in HPV58 E7 are probably risk factors associated with the development of cervical cancer in Chinese women. The presence of HPV58/52 E6 and E7 variants may be different in Chinese women.

Introduction

It has been established by molecular biological and epidemiological studies that infection with specific types of genital human papillomavirus (HPV) is an essential etiological factor for both cervical cancer and its precursor lesions, cervical intraepithelial neoplasia (CIN) [1], [2], [3]. HPV16 and 18 are the most common cancer-associated types, accounting for about 70% of all cervical cancers worldwide whereas HPV 58 and 52 infections only for 0–3% [4]. However, accumulated studies have shown that HPV 52 and 58 are relatively more frequent among HPV-positive Chinese and other Asian women and there is 11.5–28% of prevalence across the full spectrum of cervical neoplasia in Chinese and Asian women [5], [6], [7], [8], [9]. It has been estimated that worldwide HPV prevalence is 10.4% in women with normal cervical cytology [10], but less than 1% of the women develop malignant lesions [11]. It is clear that persistent infection with specific high-risk HPV types is a strong marker for progressive CIN disease [12], whereas recent studies have revealed that persistence of high-risk HPV infection might be associated with virus intratype variants.

The HPV intratype variants are defined as having nucleotide sequence variations no more than 2% in the coding region and 5% in the non-coding regions of the viral genome with respect to the prototype [13]. Concerning HPV intratype variants, the most extensive studies have been conducted on HPV16, followed by HPV18 [14]. It has been found that HPV16 included five major phylogenetic branches: European (E), Asian (As), Asian-American (AA), African-1 (Af1), and African-2 (Af2), and a few minor branches such as North American-1(NA1) [15]. These variants may differ among certain biologic and biochemical properties.

The evidence that specific intratype HPV genome variations may influence persistence of viral infection and cervical lesions progress from precursor lesion to cancer was revealed by independent studies [16], [17], [18]. The study by Londesborough and his colleagues indicated that persistent HPV16 infection and/or cervical high-grade lesions were predominantly associated with the variant T350G (L83V, leucine → valine) where the Arabic numerals represented the nucleotide or amino acid position and the letter preceding this number refers to the reference base or amino acid derived from the prototype sequence and the letter following it refers to its substitution. HPV onco-proteins E6 and E7 are essential factors for HPV-induced cellular immortalization, transformation, and carcinogenesis. The studies from European and American women have shown that specific HPV16 E6 and E7 variants may carry a higher risk for the development of invasive cervical cancer and cervical intraepithelial neoplasia in a given population [15], [16], [19], [20]. The current data on HPV variants are derived mainly from HPV16, the most common type worldwide, whereas there are few reports on HPV 58 or 52 variations. Considering relatively higher prevalence of HPV 58 and 52 in Chinese and Asian women, we investigated the sequence variations of HPV58 and 52 in Chinese women and analyzed the association between viral intratype variations and cervical cancer, as well as CIN, so as to explore influence of HPV 58 and 52 variations on the development of cervical cancer.

Section snippets

Study subjects and sample collection

During April 2008 and December 2009, a total of 2021 HPV positive cervical samples were collected from colposcopy clinic in Women's Hospital, Medical School, Zhejiang University, eastern China. The population studied ranged in age of 21–73 years with a mean of 38 years. The study was approved by the Women's Hospital Ethical Committee and informed consent was taken from each of the subjects. All subjects were examined by colposcopy and biopsy samples were taken from suspicious lesions for

Characteristics of the study subjects and HPV58/52 distribution

A total of 2021 samples from Chinese women with HR-HPV positive were enrolled in the study, including 1597 women with tissue samples and 424 women with cytology samples. Of those, there were 177 samples with single HPV58 positive and 121 with single HPV52 positive after HPV genotyping. Samples with multiple HPV infections were excluded to avoid confounding the results. In all single HPV58 and 52 positive subjects, 187 (62.8%), median age 37 years (range 22–57), were normal controls including 92

Discussion

It has been revealed that the specific E6 and E7 variants in HPV16 and 18, most common types accounting for about 70% of all cervical cancers worldwide, may carry a higher risk for the development of invasive cervical cancer and its precursors in a given population [15], [20], [30], [31]. HPV58 and 52 are relatively prevalent genotypes in Asian including Chinese women [8]. Recently, a few studies have analyzed the sequence variations in E6 and E7 genes of HPV 58 and 52, and found their risk

Conflict of interest statement

The authors declare that there are no conflicts of interest.

Acknowledgments

This work was supported in part by the Agency of Science and Technology of Zhejiang Province, Key and High Incidence of Disease Prevention and Control Techniques Special, China (No. 2006C13080); by the National Natural Science Foundation of China (Nos. 30872752 and 30973173); by the National Key Basic Research Development Plan-“973” Plan of China (No. 2009CB521800); and by the Agency of Science and Technology of Zhejiang Province, China (No. 2009c33024).

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Among these mutations, E6 A388C (K93N) and E7 C632T/G760A (T20I/G63S) might be associated with cervical neoplasia according the research result of Ding et al. in which they investigated HPV-58 E6/E7 variants originating from eastern Chinese women (Ding et al., 2010). Although previous studies regarding HPV58 E6/E7 gene variations have found their risk association with the development of cervical neoplasia (Bae, 2009; Ding et al., 2010; Wu et al., 2009), the correlative sites of E6/E7 which have been found as a risk factor for the progression of cervical cancer are different in the above studies. This may be associated with specific geographic regions and populations (Xi et al., 2006).
HPV accounts for most of incidence of cervical cancer. Genetic variations of E6 and E7 may be associated with the development of cervical cancer in specific geographic regions. HPV-58 has been found to be a relatively prevalent high-risk HPV among southwest Chinese women. To explore gene intratypic variations and polymorphisms of HPV-58 E6 and E7 genes originating in Southwest China, a total of 2000 scraped cell samples were collected for DNA extraction and HPV typing. Then, the E6 and E7 genes of HPV-58 (n = 22) were sequenced and compared to others submitted to GenBank, followed by an analysis of the diversity of secondary structure by DNASTAR software. Phylogenetic trees were then constructed by Neighbor-Joining and the Kimura 2-parameters methods, followed by an analysis of selection pressures acting on the E6/E7 genes by PAML software. 22 were HPV-58 positive among 215 high-risk types’ samples. The nucleotide variation rate of E6 was 86.36% (19/22) among the 22 HPV-58 E6 sequences studied. 4 single nucleotide changes were identified among the E6 sequences with 3/4 synonymous mutations (C187T, A260C, C307T) and 1/4 non-synonymous mutations (A388C, from Lys to Asn, in alpha helix). The most common mutations of E6 genes are the C307T and A388C. 8 single nucleotide changes were identified among the HPV-58 E7 sequences with 2/8 synonymous mutations (T726C, T744G) and 6/8 non-synonymous mutations (G599A, C632T, G694A, G760A, G761A, T803C). The nucleotide variation rate of E7 was 72.73% (17/22). The most common mutations of E7 genes are C632T, G694A, T744G, G760A (from Gly to Ser, in turn), G761A and T803C. The phylogenetic analyses demonstrate that all HPV-58 E6/E7 variants identified belonged to the Southeast Asia lineage. There was no evidence of positive selection in the sequence alignment of HPV-58 E6 and E7 genes.
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Infection with certain types of human papillomaviruses (HPVs) is a risk factor for the development of cervical cancer. HPV type 58 (HPV 58) is prevalent among Chinese women. The intratype sequence variants differ in oncogenic potential and their prevalences vary across geographic regions. The objective of this study was to analyze the variations of HPV 58 E6, E7, L1 genes and long control region (LCR) in a large samples collected from northeastern Chinese women with cervical lesions. A total of 2938 cervical samples were collected and tested for HPV type using a chip hybridization assay. The E6, E7, L1 genes and LCR of HPV 58 strains were amplified and the amplicons were subjected to direct nucleotide sequencing for variation identification. A total of 235 specimens were HPV 58 positive. High proportions of HPV 58 E6 (83.8%), E7 (76.7%), L1 (90.8%) genes and LCR (91.4%) variants were identified in strains from Chinese women. The most frequently observed variations were C307T (52.4%) in E6, T744G (74.9%) in E7, A6014C (56.9%) in L1 genes and C7266T, A7714G (55.2%) in LCR. For the E6 gene, nine nucleotide variations were identified. Among them, the A140G (T11A), A184C (E25D), G266C (V53L) and A313G were novel variations. Sequencing of the E7 gene revealed four typical nucleotide changes: G761A (G63D), G694A (G41R), T803C (V77A) and T744G. In the L1 gene, 39 nucleotide variations and 13 amino acid substitutions were identified. Among these mutations, 21 variations are reported here for the first time. Lineage A of HPV 58 was found in 142 of 174 strains (81.6%). The most prevalent HPV 58 variants in Chinese northeastern women belongs to lineage A. Novel variations in E6 and L1 genes were also reported. These findings provide new data regarding E6 and L1 gene variations of HPV 58 from women in northeast China.
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Distribution of human papillomavirus 58 and 52 E6/E7 variants in cervical neoplasia in Chinese women

Abstract

Objectives

Methods

Results

Conclusions

Introduction

Section snippets

Study subjects and sample collection

Characteristics of the study subjects and HPV58/52 distribution

Discussion

Conflict of interest statement

Acknowledgments

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