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Human Papillomavirus 16 Lineage D is Associated with High Risk of Cervical Cancer in the Brazilian Northeast Region

Papillomavirus humano 16 da linhagem D associado a alto risco de câncer de colo do útero em região do nordeste brasileiro

Abstract

Objective

Similar to Human Papillomavirus (HPV) genotypes, different lineages of a genotype also have different carcinogenic capabilities. Studies have shown that specific genotype lineages of oncogenic HPV are associated with variable risks for the development of cervical intraepithelial neoplasia (CIN2/CIN3) and cervical cancer. The present study aimed to analyze the genetic diversity of the HPV16 genotype in women with CIN2/CIN3 and cervical cancer, from the northeast region of Brazil.

Methods

A cross-sectional multicenter study was conducted in the northeast region of Brazil, from 2014 to 2016. This study included 196 cases of HPV16 variants (59 and 137 cases of CIN2/CIN3 and cervical cancer, respectively). The difference of proportion test was used to compare patients with CIN2/CIN3 and cervical cancer, based on the prevalent HPV16 lineage (p < 0.05).

Results

According to the histopathological diagnosis, the percentage of lineage frequencies revealed a marginal difference in the prevalence of lineage A in CIN2/CIN3, compared with that in cervical cancer (p = 0.053). For lineage D, the proportion was higher in cancer cases (32.8%), than in CIN2/CIN3 cases (16.9%), with p = 0.023.

Conclusion

HPV16 lineage A was the most frequent lineage in both CIN2/CIN3 and cervical cancer samples, while lineage D was predominant in cervical cancer, suggesting a possible association between HPV16 lineage D and cervical cancer.

Keywords
HPV16; lineage A; lineage D; CIN2/CIN3; cervical cancer

Resumo

Objetivo

Tanto os tipos quanto as linhagens do Papilomavírus Humano (HPV) parecem ter diferentes capacidades carcinogênicas e estão associados a riscos variados para o desenvolvimento de neoplasia intraepitelial cervical (NIC) e câncer de colo do útero. O presente estudo tem como objetivo analisar a diversidade genética do genótipo HPV 16 nos casos de NIC2/NIC3 e câncer de colo de útero em mulheres da região Nordeste do Brasil.

Métodos

Estudo transversal de base hospitalar realizado na região Nordeste do Brasil no período de 2014 a 2016. A amostra foi composta por 196 casos da variante HPV-16 (59 casos de NIC2/NIC3 e 137 de câncer do colo do útero). O teste de diferença de proporção foi usado para comparar os grupos NIC2/NIC3 e câncer de colo do útero por linhagem viral em relação à prevalência da linhagem HPV-16. Foi considerada significância estatística o valor de p < 0,05.

Resultados

As frequências de linhagem por diagnóstico histopatológico mostraram diferença limítrofe da linhagem A no grupo NIC2/NIC3 em relação ao grupo câncer de colo de útero (p = 0,053). Por outro lado, em relação à linhagem D, houve uma proporção maior nos casos de câncer (32,8%) quando comparado ao grupo NIC2/NIC3 (16,9%) e esta diferença se mostrou estatisticamente significante (p = 0,023).

Conclusão

A linhagem A do HPV-16 foi a mais frequente tanto nas amostras CIN2/CIN3 quanto nas amostras de câncer de colo de útero, enquanto a linhagem D predominou no câncer de colo do útero, sugerindo uma possível associação da linhagem D de HPV-16 com câncer de colo de útero.

Palavras-chave
HPV16; linhagem A; linhagem D; NIC2/NIC3; câncer colo útero

Introduction

Cervical cancer is the fourth most common cancer, in terms of incidence and mortality, among women worldwide.11 Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(03):209–249. Doi: 10.3322/caac.21660
https://doi.org/10.3322/caac.21660...
In Brazil, it is the third and fourth most common cancer among women, in terms of incidence and mortality, respectively.22 INCA, Instituto Nacional de Câncer. Estimativa 2022: incidência de câncer no Brasil / Instituto Nacional de Câncer. – Rio de Janeiro: INCA, 2019. Available on: https://www.gov.br/inca/pt-br/assuntos/cancer/numeros/estimativa
https://www.gov.br/inca/pt-br/assuntos/c...
,33 INCA, Instituto Nacional de Câncer José Alencar Gomes da Silva. Coordenação de Prevenção e Vigilância. Divisão de Informação. Atlas de mortalidade por câncer: versão 2014. Rio de Janeiro: INCA, 2014. Available on: <https:/https://www.inca.gov.br/app/mortalidade>. Available: 21 dec. 2022
https://www.inca.gov.br/app/mortalidade...
Several studies have shown that the Human Papillomavirus (HPV) is a predominant, but not the only, factor for cervical cancer development. The viral genotype HPV16 is the most prevalent in cervical cancer and is considered a Group 1 carcinogenic agent for humans by the International Agency for Cancer Research.44 Schiffman M, Clifford G, Buonaguro FM. Classification of weakly carcinogenic human papillomavirus types: addressing the limits of epidemiology at the borderline. Infect Agent Cancer. 2009;4:8. Doi: 10.1186/1750-9378-4-8
https://doi.org/10.1186/1750-9378-4-8...
The study of the genetic diversity of HPV16 has enabled the characterization of specific viral lineages associated with a higher risk of cervical intraepithelial neoplasia (CIN2/CIN3) and cervical cancer development.55 Xi LF, Koutsky LA, Hildesheim A, Galloway D, Wheeler CM, Winer RL, et al. Risk for high-grade cervical intraepithelial neoplasia associated with variants of human papillomavirus types 16 and 18. Cancer Epidemiol Biomarkers Prev. 2007;16(01):4–10. Doi: 10.1158/1055-9965.EPI-06-0670
https://doi.org/10.1158/1055-9965.EPI-06...
88 Clifford GM, Tenet V, Georges D, Alemany L, Pavón MA, Chen Z, et al. Human papillomavirus 16 sub-lineage dispersal and cervical cancer risk worldwide: Whole viral genome sequences from 7116 HPV16-positive women. Papillomavirus Res. 2019;7: 67–74. Doi: 10.1016/j.pvr.2019.02.001
https://doi.org/10.1016/j.pvr.2019.02.00...
For HPV16, the lineages were initially named according to their geographical prevalence and separated into five groups: European (EUR), Asian (As), Asian-American (AA), African 1 (Af1), and African 2 (Af2).99 Ho L, Chan SY, Burk RD, Das BC, Fujinaga K, Icenogle JP, et al. The genetic drift of human papillomavirus type 16 is a means of reconstructing prehistoric viral spread and the movement of ancient human populations. J Virol. 1993;67(11):6413–6423. Doi: 10.1128/JVI.67.11.6413-6423.1993
https://doi.org/10.1128/JVI.67.11.6413-6...
1212 Cornet I, Gheit T, Franceschi S, Vignat J, Burk RD, Sylla BS, et al; IARC HPV Variant Study Group. Human papillomavirus type 16 genetic variants: phylogeny and classification based on E6 and LCR. J Virol. 2012;86(12):6855–6861. Doi: 10.1128/JVI.00483-12
https://doi.org/10.1128/JVI.00483-12...
In 2013, Burk et al., proposed a new α-numeric nomenclature for all HPV lineages based on the differences in the complete viral genome sequence.1313 Burk RD, Harari A, Chen Z. Human papillomavirus genome variants. Virology. 2013;445(1-2):232–243. Doi: 10.1016/j. virol.2013.07.018
https://doi.org/10.1016/j.virol.2013.07....
The lineages for HPV16 were renamed as follows: A (corresponding to EUR and As), B (corresponding to Af1), C (corresponding to Af2), and D (corresponding to AA).

Studies have shown that HPV16 lineages B, C, and D with higher pathogenicity are associated with a higher viral persistence, compared with the lineage A.44 Schiffman M, Clifford G, Buonaguro FM. Classification of weakly carcinogenic human papillomavirus types: addressing the limits of epidemiology at the borderline. Infect Agent Cancer. 2009;4:8. Doi: 10.1186/1750-9378-4-8
https://doi.org/10.1186/1750-9378-4-8...
,1414 Sichero L, Ferreira S, Trottier H, Duarte-Franco E, Ferenczy A, Franco EL, et al. High grade cervical lesions are caused preferentially by non-European variants of HPVs 16 and 18. Int J Cancer. 2007;120(08):1763–1768. Doi: 10.1002/ijc.22481
https://doi.org/10.1002/ijc.22481...
,1515 Villa LL, Sichero L, Rahal P, Caballero O, Ferenczy A, Rohan T, et al. Molecular variants of human papillomavirus types 16 and 18 preferentially associated with cervical neoplasia. J Gen Virol. 2000;81(Pt 12):2959–2968. Doi: 10.1099/0022-1317-81-12-2959
https://doi.org/10.1099/0022-1317-81-12-...
Additionally, the HPV16 lineages B, C, and D are also associated with a higher risk of CIN2/CIN3 and cervical cancer.1414 Sichero L, Ferreira S, Trottier H, Duarte-Franco E, Ferenczy A, Franco EL, et al. High grade cervical lesions are caused preferentially by non-European variants of HPVs 16 and 18. Int J Cancer. 2007;120(08):1763–1768. Doi: 10.1002/ijc.22481
https://doi.org/10.1002/ijc.22481...
,1616 Freitas LB, Chen Z, Muqui EF, Boldrini NAT, Miranda AE, Spano LC, et al. Human papillomavirus 16 non-European variants are preferentially associated with high-grade cervical lesions. PLoS One. 2014;9(07):e100746. Doi: 10.1371/journal.pone.0100746
https://doi.org/10.1371/journal.pone.010...
,1717 Junes-Gill K, Sichero L, Maciag PC, Mello W, Noronha V, Villa LL. Human papillomavirus type 16 variants in cervical cancer from an admixtured population in Brazil. J Med Virol. 2008;80(09): 1639–1645 The D lineage is also associated with adenocarcinoma.1818 Tornesello ML, Losito S, Benincasa G, et al. Human papillomavirus (HPV) genotypes and HPV16 variants and risk of adenocarcinoma and squamous cell carcinoma of the cervix. Gynecol Oncol. 2011; 121(01):32–42. Doi: 10.1016/j.ygyno.2010.12.005
https://doi.org/10.1016/j.ygyno.2010.12....
A longitudinal study has shown that the HPV16 sub-lineages D2 and D3 are more significantly associated with CIN2/CIN3 and cervical cancer, compared with other lineages/sub-lineages.1616 Freitas LB, Chen Z, Muqui EF, Boldrini NAT, Miranda AE, Spano LC, et al. Human papillomavirus 16 non-European variants are preferentially associated with high-grade cervical lesions. PLoS One. 2014;9(07):e100746. Doi: 10.1371/journal.pone.0100746
https://doi.org/10.1371/journal.pone.010...
,1919 Mirabello L, Yeager M, Yu K, Clifford GM, Xiao Y, Zhu B, et al. HPV16 E7 Genetic conservation is critical to carcinogenesis. Cell. 2017;170(06):1164–1174.e6. Doi: 10.1016/j.cell.2017.08.001
https://doi.org/10.1016/j.cell.2017.08.0...
Similar characteristics were reported in lineages of other HPV genotypes, such as HPV 18 and HPV 45.2020 Wentzensen N, Sun C, Ghosh A, Kinney W, Mirabello L, Wacholder S, et al. Methylation of HPV18, HPV31, and HPV45 genomes and cervical intraepithelial neoplasia grade 3. J Natl Cancer Inst. 2012; 104(22):1738–1749. Doi: 10.1093/jnci/djs425
https://doi.org/10.1093/jnci/djs425...

In this study, we analyzed the genetic diversity of the HPV16 genotype in CIN2/CIN3 and cervical cancer cases in women from the northeast region of Brazil. In this region, cervical cancer was ranked second in terms of cancer incidence, excluding nonmelanoma skin cancer (20.48/100,000),22 INCA, Instituto Nacional de Câncer. Estimativa 2022: incidência de câncer no Brasil / Instituto Nacional de Câncer. – Rio de Janeiro: INCA, 2019. Available on: https://www.gov.br/inca/pt-br/assuntos/cancer/numeros/estimativa
https://www.gov.br/inca/pt-br/assuntos/c...
and first in terms of mortality due to cancer (9.52/100.000) among women, in 2020.33 INCA, Instituto Nacional de Câncer José Alencar Gomes da Silva. Coordenação de Prevenção e Vigilância. Divisão de Informação. Atlas de mortalidade por câncer: versão 2014. Rio de Janeiro: INCA, 2014. Available on: <https:/https://www.inca.gov.br/app/mortalidade>. Available: 21 dec. 2022
https://www.inca.gov.br/app/mortalidade...
The present work was part of a multicenter study on the HPV genotypes prior to the introduction of the HPV vaccine in the National Immunization Program, which was performed in two other cities in Brazil (Rio de Janeiro and Belém).2121 de Almeida LM, Martins LFL, Pontes VB, Corrêa FM, Montenegro RC, Pinto LC, et al. Human Papillomavirus Genotype Distribution among Cervical Cancer Patients prior to Brazilian National HPV Immunization Program. J Environ Public Health. 2017; 2017:1645074. Doi: 10.1155/2017/1645074
https://doi.org/10.1155/2017/1645074...
,2222 Pontes VB, Martins LFL, Szklo M, Moreira MÂM, Chaves CBP, de Almeida LM. Factors associated with cervical intraepithelial neoplasia (CIN2/CIN3), early stage and advanced stage of cervical cancer diagnosis in the Brazilian Amazonian region. Eur J Cancer Prev. 2020;29(04):342–345. Doi: 10.1097/CEJ.0000000000000546
https://doi.org/10.1097/CEJ.000000000000...

Methods

A cross-sectional multicenter study was performed at two hospitals for cancer treatment in Cidade do Recife, Pernambuco, Brazil, between July 2014 and December 2016.

Women ≥18 years old, with pap smear tests indicative of high-grade intraepithelial lesion (HGL; CIN2/CIN3) or cervical cancer, and who were referred for a colposcopy exam, were invited to participate in the present study. Women who underwent a biopsy and were diagnosed for CIN2/CIN3 or cervical cancer, based on histopathological examination, were included in this analysis. The exclusion criteria included women previously treated for cervical cancer (cancer surgery, radiotherapy, or chemotherapy) or those with cognitive or physical disabilities that could prevent them from answering a questionnaire.

After receiving signed consent, the women were interviewed by trained nurses using an epidemiological questionnaire. We collected data about their socioeconomic status, knowledge about cervical cancer prevention, access to healthcare services for diagnosis and treatment, hormonal and reproductive histories, and tobacco usage. Additional clinical information was obtained from their medical records. The biopsy samples were stored in RNALater until nucleic acid isolation, and were then sent to the research laboratory of the hospital.

DNA was isolated from the biopsy samples using the QIAamp DNA Mini Kit (Qiagen; Cat. Number 51306, North Rhine-Westphalia, Germany). HPV was detected through PCR amplification using the primer sets PGMY07 and PGMY09,2323 Gravitt PE, Peyton CL, Alessi TQ, Wheeler CM, Coutlée F, Hildesheim A, et al. Improved amplification of genital human papillomaviruses. J Clin Microbiol. 2000;38(01):357–361. Doi: 10.1128/JCM.38.1.357-361.2000
https://doi.org/10.1128/JCM.38.1.357-361...
whereas reactions without PCR products underwent nested PCR, using the primers GP5 +/GP6 + .2424 de Roda Husman AM, Walboomers JM, van den Brule AJ, Meijer CJ, Snijders PJ. The use of general primers GP5 and GP6 elongated at their 3' ends with adjacent highly conserved sequences improves human papillomavirus detection by PCR. J Gen Virol. 1995;76(Pt 4):1057–1062. Doi: 10.1099/0022-1317-76-4-1057
https://doi.org/10.1099/0022-1317-76-4-1...
Samples negative for HPV DNA amplification after nested PCR were subjected to PCR for β-globin, and samples positive for β-globin and negative for HPV through nested PCR were considered negative for HPV. For HPV identification, the PCR products were purified using the Illustra GFX PCR DNA and Gel Band Purification Kit (GE Healthcare; Cat. Number 28403471, Buckinghamshire, UK), and were further subjected to DNA sequencing in both directions, using the Big Dye Terminator Cycle Sequencing Ready Reaction V3.1 Kit (Applied Biosystems; Cat. Number 4336919, Texas, USA), as per manufacturer's instructions, and sequenced in an ABI 3730xL DNA Analyzer (Applied Biosystems, Osaka, Japan). The electropherograms of each sample were checked manually and a consensus sequence of the bidirectional sequencing was subjected to HPV genotype identification using the Blast software (https://blast.ncbi.nlm.nih.gov/Blast.cgi).2525 Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ. Basic local alignment search tool. J Mol Biol. 1990;215(03):403–410. Doi: 10.1016/S0022-2836(05)80360-2
https://doi.org/10.1016/S0022-2836(05)80...

Among the 415 samples evaluated for HPV genotyping through DNA sequencing, the 8 most common types were: HPV16 (58.6%), HPV45 (7.2%), HPV18 (7.0%), HPV35 (4.6%), HPV58 (3.6%), HPV31 (3.1%), HPV33 (2.7%), and HPV52 (2.4%). HPV16 was the most common HPV genotype in CIN2/CIN3 (53.9%) and cervical cancer (60.7%). A total of 243 samples contained the HPV16 genotype, and 196 samples (80.7%) were further assessed to identify their lineages.

Samples exhibiting the HPV16 genotypes were subjected to PCR amplification of the viral genomic regions LCR and E6, in two overlapping fragments, as previously described.2626 Vidal JP, Felix SP, Chaves CB, Patury P, Franco VF, Morais EA, et al. Genetic diversity of HPV16 and HPV18 in Brazilian patients with invasive cervical cancer. J Med Virol. 2016;88(07):1279–1287. Doi: 10.1002/jmv.24458
https://doi.org/10.1002/jmv.24458...
The resultant sequence, obtained by sequencing the overlapping fragments, was aligned to HPV16 lineage reference sequences suggested by Burk et al.1313 Burk RD, Harari A, Chen Z. Human papillomavirus genome variants. Virology. 2013;445(1-2):232–243. Doi: 10.1016/j. virol.2013.07.018
https://doi.org/10.1016/j.virol.2013.07....
HPV16 lineage identification was performed by detecting a sequence signature (the presence of specific nucleotides at specific sequence positions), as previously described.1212 Cornet I, Gheit T, Franceschi S, Vignat J, Burk RD, Sylla BS, et al; IARC HPV Variant Study Group. Human papillomavirus type 16 genetic variants: phylogeny and classification based on E6 and LCR. J Virol. 2012;86(12):6855–6861. Doi: 10.1128/JVI.00483-12
https://doi.org/10.1128/JVI.00483-12...
HPV16 lineage nomenclature used in this study followed those provided by Burk et al.1313 Burk RD, Harari A, Chen Z. Human papillomavirus genome variants. Virology. 2013;445(1-2):232–243. Doi: 10.1016/j. virol.2013.07.018
https://doi.org/10.1016/j.virol.2013.07....

The epidemiological data were stored using Epi Info 3.5.1 and then linked to both the clinical and HPV DNA sequence data. The final database was analyzed using Stata v.15.0. the chi-squared test (or the Fisher exact test) was used to compare the distribution of the patients based on selected characteristics, according to their histopathological diagnosis. The ratio difference test was used to compare the prevalence of HPV16 viral strains, considering two groups: CIN2/CIN3 and cervical cancer (p < 0.05). The B and C lineages were grouped due to low frequency.

All study procedures were approved by the Institutional Ethics Committees at both hospitals (CAAE 24687713.8.0000.5201 and CAAE 40349014.0.0000.5205).

Results

Selected characteristics of the 196 female patients included in the present study, according to disease status (CIN2/CIN3 versus cervical cancer), are presented in Table 1. We observed that the women diagnosed with CIN2/CIN3 were younger than those diagnosed with cervical cancer. No statistical differences were found between the women with CIN2/CIN3 and cervical cancer for oral contraceptive use or tobacco exposure. The number of childbirths was greater in women with cervical cancer than in those with CIN2/CIN3.

Table 1
Distribution of female patients based on selected characteristics, according to their histopathological diagnosis

The LCR and E6 regions of each sample with an HPV16 genotype were aligned with HPV16 reference sequences representing the lineages A, B, C, and D, and the presence of specific SNPs was used to identify HPV16 lineages present in each sample. The distribution of the HPV16 lineages is as follows: lineage A, 130 women; lineage B, 1 woman; lineage C, 10 women; and lineage D, 55 women. We observed distinct frequencies of HPV16 lineages between CIN2/CIN3 and cervical cancer, with lineage A being more frenquent in CIN2/CIN3 (p = 0.053). Moreover, based on the histopathological diagnosis, the comparison of HPV16 lineage frequencies showed a higher proportion of the D lineage in cervical cancer than that in CIN2/CIN3 (p = 0.023) (Table 2).

Table 2
Distribution of female patients, according to HPV16 lineage frequencies and their histopathological diagnosis

Discussion

The lineage A of HPV16 was the most frequent in the samples examined in the present study, for both CIN2/CIN3 and cervical cancer, while lineage D was predominant in cervical cancer samples, suggesting an association between the lineage D of HPV16 and cervical cancer.

The genetic variations in HPV16 can influence the risk of cervical cancer, which vary based on the different lineages or sublineages present in different regions of the world.88 Clifford GM, Tenet V, Georges D, Alemany L, Pavón MA, Chen Z, et al. Human papillomavirus 16 sub-lineage dispersal and cervical cancer risk worldwide: Whole viral genome sequences from 7116 HPV16-positive women. Papillomavirus Res. 2019;7: 67–74. Doi: 10.1016/j.pvr.2019.02.001
https://doi.org/10.1016/j.pvr.2019.02.00...
Previous studies attempted to demonstrate an association between non-European lineages (B/C/D) and a higher risk for developing CIN2/CIN31414 Sichero L, Ferreira S, Trottier H, Duarte-Franco E, Ferenczy A, Franco EL, et al. High grade cervical lesions are caused preferentially by non-European variants of HPVs 16 and 18. Int J Cancer. 2007;120(08):1763–1768. Doi: 10.1002/ijc.22481
https://doi.org/10.1002/ijc.22481...
,1717 Junes-Gill K, Sichero L, Maciag PC, Mello W, Noronha V, Villa LL. Human papillomavirus type 16 variants in cervical cancer from an admixtured population in Brazil. J Med Virol. 2008;80(09): 1639–1645 and cervical cancer,1717 Junes-Gill K, Sichero L, Maciag PC, Mello W, Noronha V, Villa LL. Human papillomavirus type 16 variants in cervical cancer from an admixtured population in Brazil. J Med Virol. 2008;80(09): 1639–1645,2727 Hildesheim A, Wang SS. Host and viral genetics and risk of cervical cancer: a review. Virus Res. 2002;89(02):229–240. Doi: 10.1016/s0168-1702(02)00191-0
https://doi.org/10.1016/s0168-1702(02)00...
compared with the European lineage (A). A major limitation of these studies was the grouping of lineages B, C, and D as non-European lineages, which did not allow the differentiation of the carcinogenic potential among these lineages. A recent study on > 3,200 women, comparing women without lesions and with CIN1 and women with CIN2 or CIN3 or invasive cancer, have reported an association between the HPV16 sub-lineages D2 and D3 and CIN3 and/or cervical cancer.1717 Junes-Gill K, Sichero L, Maciag PC, Mello W, Noronha V, Villa LL. Human papillomavirus type 16 variants in cervical cancer from an admixtured population in Brazil. J Med Virol. 2008;80(09): 1639–1645 Clifford et al. analyzed samples from > 7,100 women, comparing those with normal cells, or atypical squamous cells of undetermined significance, or low-grade squamous intraepithelial lesions or CIN1, with those with invasive cervical cancer, and found an association between the HPV16 lineage D and sublineage A4 and cancer diagnosis.88 Clifford GM, Tenet V, Georges D, Alemany L, Pavón MA, Chen Z, et al. Human papillomavirus 16 sub-lineage dispersal and cervical cancer risk worldwide: Whole viral genome sequences from 7116 HPV16-positive women. Papillomavirus Res. 2019;7: 67–74. Doi: 10.1016/j.pvr.2019.02.001
https://doi.org/10.1016/j.pvr.2019.02.00...

A recent study on Croatian women confirmed that HPV16, mainly belonging to the European branch, was most frequently associated with histologically confirmed high-grade intraepithelial lesions (CIN2 or CIN3) and cervical cancer.2828 KaradžaM, Židovec Lepej S, Planinić A, Grgić I, Ćorušić A, Planinić Pavao, et al. Distribution of human papillomavirus genotypes in women with high-grade cervical intraepithelial lesions and cervical carcinoma and analysis of human papillomavirus-16 genomic variants. Croat Med J. 2021;62(01):68–79. Doi: 10.3325/cmj.2021.62.68
https://doi.org/10.3325/cmj.2021.62.68...

In the present study, the lineage A of HPV16 was the most frequently detected lineage, and although it was associated with high-grade lesions (CIN2/CIN3), we could not demonstrate a difference between these high-grade lesions and cervical cancer. Another study conducted in a different region in Brazil also found a high prevalence of the lineage A of HPV16 in samples of high- and low-grade lesions, including cervical cancer.2929 de Oliveira GR, Vieira VC, Ávila EC, Finger-Jardim F, Caldeira TD, Gatii FA, et al. Human papillomavirus type distribution and HPV16 intratype diversity in southern Brazil in women with and without cervical lesions. Mem Inst Oswaldo Cruz. 2017;112 (07):492–498. Doi: 10.1590/0074-02760160530
https://doi.org/10.1590/0074-02760160530...

In contrast, the D lineage of HPV16 showed a significant association with cervical cancer, compared with high-grade lesions, suggesting that the lineage D of HPV16 is involved in the progression of HPV16 infection to cervical cancer. Although this is a cross-sectional study, the present study provides novel data on the association between specific lineages of HPV16 and cervical cancer. Our data suggest that the lineage D could be more aggressive with respect to the progression of high-grade lesions into cancer, without restricting the association from linking normal/low grade lesions and invasive cancer.

Conclusion

The A lineage of HPV16 was the most frequent in both the CIN2/CIN3 and cervical cancer samples, whereas the lineage D of HPV16 was predominant in cervical cancer, suggesting an association between HPV16 lineage D and cervical cancer.

Acknowledgments

We would like to thank Antônio Maria S. Negrão, Neile A. de Carvalho, Evaneide A. de Morais, and all nurses for their contribution to the execution of the study. Moreover, we would like to thank the people of Pernambuco Cancer Hospital and Instituto de Medicina Integral Prof. Fernando Figueira (IMIP) for their support during the study. We also would like to thank Editage (www.editage.com) for English language editing. The present study was financially supported by the following grants: OPAS/INCA, CEPESC: no. BR/LOA/1200085–001; Instituto Nacional de Ciência e Tecnologia para Controle do Câncer (INCT-Cancer Control); Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, grants: 573806/2008–0 and 304339/2018–0); Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ, grants: E26/170.026/2008 and 200.928/2021).

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Publication Dates

  • Publication in this collection
    09 Oct 2023
  • Date of issue
    2023

History

  • Received
    06 Jan 2023
  • Accepted
    08 Mar 2023
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