Human papillomavirus type 16 sequence variation in cervical cancers: a worldwide perspective

Abstract

We examined intratype human papillomavirus type 16 (HPV-16) sequence variation in tumor samples that were collected and analyzed in an international study of invasive cervical cancer. The collection included tumors from 22 countries in five continents. Using our recently developed E6 and L1 PCR-based hybridization systems to distinguish HPV-16 variant lineages, we analyzed material from tumors previously found to contain HPV-16 DNA. Of 408 specimens analyzed in the E6 hybridization assay, 376 (92.2%) belonged to previously reported HPV-16 variant lineages. The remaining 32 specimens (7.8%) harbored HPV-16 variants with novel hybridization patterns, novel nucleotide changes, or both. Nucleotide sequences (1,203 bp) were determined for the E6, the MY09/11 region of L1, and the long control region of each novel variant and representative specimens from each hybridization pattern observed. Based on E6 hybridization patterns, most of the variants from European and North American samples were phylogenetically classified as European prototype (E) while samples from Africa contained primarily African 1 (Af1) or African 2 (Af2) variants. The majority of Asian (As) variants were observed in Southeast Asia, and almost all Asian American (AA) variants were from Central and South America or Spain. A single North American 1 (NA1) variant was detected in a tumor from Argentina. Nucleotide changes previously shown to covary between the MY09/11 region of L1 and the E6 coding region were examined in a subset of 249 specimens. We observed 22 combined E6-L1 hybridization patterns, of which 11 (in 21 samples) were novel. No unanticipated nucleotide covariation was observed between the E class and the AA-Af1-Af2-NA1 classes, suggesting the absence or rarity of genomic recombination between HPV-16 lineages. This extensive description of HPV-16 variants forms a basis for further examining the relationship between intratype variation and basic functional differences in biological activities. HPV-16 variants may prove important for the determination of the risk of cervical neoplasia and for the design of HPV-16 vaccine strategies.

Association of HPV16 E6 variants with diagnostic severity in cervical cytology samples of 354 women in a US population

“…While the US population is quite diverse, HPV16 European sequences have dominated most variant analyses. [6][7][8]12,19,26 Given that the prevalence of cervical cancer varies in different regions and countries, a number of studies have addressed the possible association of HPV16 variant status with different risks for progression to malignancy. This interest was based on the association of amino acid differences with some DNA sequences, suggesting the possibility that tertiary structure changes in viral proteins or alterations in control elements in the LCR can affect the biological activity or immunologic characteristics of associated lesions.…”

“…Although our data confirm the increased association of NE variants with high grade cervical lesions, in fact, most of our cancer cases harbored EP or EV sequences, as has been reported by others in US 7,11,19 and European populations. 7,26,34,35 The most frequent HPV16 E6 pattern reported to date in cancers from China 36,37 and Japan 38 is the As variant that is closely related to EP with a wide prevalence in Asia. Those populations reporting large numbers of women with cancers harboring AA variants, such as Mexico 18 and other areas of Central and South America 7 in fact have high prevalence of AA variants overall.…”

“…A variant category was assigned for each case relative to the prototype nucleotide sequence 5 which has been subsequently modified as HPV16R, 25 as well as published HPV16 E6 sequence patterns that define the different variants. [6][7][8] European categories included EP and EV patterns based on a small number of nucleotide differences, while the NE categories included AA, NA-1, AF-1, and AF-2. The As variant which differs from the EP by 1 nucleotide (178 TfiG) 6 was grouped with EV.…”

The clinical importance of the nomenclature, evolution and taxonomy of human papillomaviruses

“…In order to identify a variant, one typically sequences a small part of the HPV genome, for example 400 bp of the long control region or the 450 bp of the E6 gene, and calls a variant every isolate that differs from the prototype by at least one nucleotide. This strategy has been applied to numerous HPV types (Ho et al, 1993;Ong et al, 1993;Heinzel et al, 1995;Stewart et al, 1996;Yamada et al, 1997;Chan et al, 1997) from isolates throughout the world. The two principal observations from these studies were that (i) there is apparently only a limited number (for example 20-100) of common variants of each HPV type, and (ii) that variants showed maximal divergence when they were sampled from ethnic groups that evolved for a long time without contact, for example Africans and American Indians.…”

Enhancer‐promoter Activity of Human Papillomavirus Type 16 Long Control Regions Isolated from Cell Lines SiHa and CaSki and Cervical Cancer Biopsies

“…4. According to the classifications described by Yamada et al, 27) the HPV-16 DNAs isolated from Japanese patients consisted of European (14 cases, 27.5%), Asian (35 cases, 68.6%) and Asian-American (2 cases, 3.9%) variants ( Fig. 4).…”