Progression of cervical intraepithelial neoplasia to cervical cancer: interactions of cytochrome P450 CYP2D6 EM and glutathione s-transferase GSTM1 null genotypes and cigarette smoking

Warwick, A.; Redman, C. W. E.; Jones, Peter W.; Fryer, Anthony A.; Gilford, Janice; Alldersea, Julie; Strange, Richard C.

doi:10.1038/bjc.1994.378

Cited by 32 publications

(22 citation statements)

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“…Os dois mecanismos principais pelo qual o hábito de fumar contribui para a oncogênese cervical incluem a exposição direta do DNA de células epiteliais cervicais a nicotina e a cotidina, e a produtos metabólicos do tipo esperado a partir de reações com hidrocarbonetos policíclicos aromáticos e aminas aromáticas, outros componentes da fumaça do cigarro 23,46 . As associações entre diferentes genótipos de enzimas carcinógenas-metabolizantes, fumo e neoplasia cervical foram investigadas por dois estudos de Warwick et al 1,56,57 . O primeiro estudo deste autor concluiu que fumantes com o genótipo tipo selvagem da enzima detoxificante citocromo P450 fase 1 (CYP2D6), genótipo metabolizador extensivo (EM), têm um risco aumentado para NIC II/III, mas um risco reduzido para carcinoma escamoso cervical invasivo 13 .…”

Section: Tabagismounclassified

“…De qualquer modo, os carcinógenos necessários para a progressão para neoplasia invasora e presumidamente efetivamente degradados por CYP2D6-EM ainda não são conhecidos. O segundo estudo realizado por Warwick et al não encontrou associação significativa entre outro genótipo da S-transferase classe theta glutationa (GSTT1) e a neoplasia cervical, da mesma forma do que foi verificado anteriormente com o genótipo S-transferase glutationa fase 2 (GSTM1), por este mesmo autor 56,57 .…”

Section: Tabagismounclassified

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Co-fatores do HPV na oncogênese cervical

Pinto¹,

Túlio²,

Cruz³

2002

Rev. Assoc. Med. Bras.

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Artigo de RevisãoRESUMO O papilomavírus humano (HPV) exerce um papel central na carcinogênese do colo uterino. Em torno a ele orbitam outros fatores que influenciam direta ou indiretamente a instalação deste mecanismo no epitélio escamoso cervical. Investigações a respeito dos mecanismos de atuação e interação desses co-fatores com os elementos virais encontram-se na literatura dos últimos 20 anos. O presente artigo de revisão explora os possíveis co-fatores do HPV na gênese do carcinoma escamoso do colo uterino, levando em conta apenas os fatores cuja associação com o vírus ou câncer cervical tenha sido documentada experimentalmente, e não apenas clínica ou epidemiologicamente. Dentre os 2,6,16,34,36,40,42,47,52,55 , bem como pelo esforço recente de pesquisadores no desenvolvimento de vacinas contra este vírus, com a finalidade de prevenção deste tipo de câncer 26,30,45,52 . A partir daí, esta revisão passa a explorar os possíveis co-fatores do HPV no processo de carcinogênese, levando em conta apenas os fatores cuja a associação com o vírus ou câncer cervical tenha sido documentada experimentalmente, e não apenas clínica ou epidemiologicamente. Por não ser o objetivo desta revisão, fatores que têm sido vinculados ao HPV por estudos puramente epidemiológicos não serão abordados. Dentre eles incluem-se o início precoce da atividade sexual, multiplicidade de parceiros, baixa escolaridade e renda, multiparidade e história de doenças sexualmente transmissíveis 8 , incluindo infecção por clamídia 33,29 . O presente trabalho visa atualizar o leitor a respeito das certezas e incertezas da literatura acerca dos principais cofatores do HPV na gênese do carcinoma escamoso de colo uterino. Fatores imunológicosVários estudos na literatura suportam a forte associação existente entre a oncogênese e progressão neoplásica relacionada ao HPV e ao sistema imunológico. Entretanto, os mecanismos exatos que disparam o gatilho de uma resposta imune eficiente contra lesões relacionadas ao HPV ainda não são conhecidos. Eles podem estar relacionados à ativação do sistema imunológico ou à composição genética do hospedeiro.Uma vez que a exposição direta das oncoproteínas do HPV a células imunocompetentes não ocorre, é concebível que o desenvolvimento de anticorpos às proteínas virais possa depender de uma infecção secundária por meio de pequenas abrasões ou soluções de continuidade do epitélio, resultando na exposição das proteínas virais a estas células. No câncer relacionado ao HPV, este mecanismo depende da ocorrência de necrose celular do tecido proliferante invasor 18 . Resposta imune localA presença de células monomorfonucleares, principalmente células CD4 e ma-

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Section: Tabagismounclassified

Co-fatores do HPV na oncogênese cervical

Pinto¹,

Túlio²,

Cruz³

2002

Rev. Assoc. Med. Bras.

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“…51 52 DiVerential cervical expression of cytochrome P450 enzymes, which activate carcinogenic nitrosamines, and glutathione S transferase, which denatures them, may play a role in determining individual susceptibility to tobacco related carcinogens. 53 …”

Section: Clinical Application Of Hpv Researchmentioning

confidence: 99%

Aetiology, pathogenesis, and pathology of cervical neoplasia.

1998

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Early epidemiological studies of cervical neoplasia suggested a causal relation with sexual activity and human papillomaviruses (HPVs) have emerged as prime suspects as venerally transmitted carcinogens. HPVs fall into two broad camps: low risk types, associated with cervical condylomas and CIN 1; and high risk types (mostly 16 and 18), found in 50-80% of CIN 2 and CIN 3 lesions, and 90% of cancers. This association with cancer is very strong, with odds ratios of > 15 (often much higher) in case-control studies that are methodologically sound. An infrequently detected third group of intermediate risk type HPVs is associated with all grades of CIN and occasionally with cancers. HPVs have also been detected in a wide range of asymptomatic controls, indicating that other events are required for development of neoplasia such as viral persistence and/or altered expression of viral genes, often following integration of the viral genome. This leaves the two major viral oncogenes, E6 and E7, directly coupled to viral enhancers and promoters, allowing their continued expression after integration. High risk HPV E7 proteins bind and inactivate the Rb protein, whereas E6 proteins bind p53 and direct its rapid degradation. A range of putative cofactors has been implicated in progression: HLA type, immunosuppression, sex steroid hormones, and smoking; most of these cofactors appear to influence progression to CIN 3. The natural history includes progression to CIN 3 in 10% of CIN 1 and 20% of CIN 2 cases, whereas at least 12% of CIN 3 cases progress to invasive carcinoma. Cervical glandular intraepithelial neoplasia (CGIN) often coexists with squamous CIN, and the premalignant potential of high grade CGIN is not in doubt, but the natural history of low grade CGIN remains uncertain. A high proportion of CGIN lesions and adenocarcinomas are HPV positive, and HPV18 has been implicated more in glandular than in squamous lesions. A strong clinical case for the application of HPV typing of cells recovered from cervical scrapes can be made; however, a rigorous cost-benefit analysis of introducing HPV typing into the cervical screening programme is required. Prophylactic and therapeutic HPV vaccines are under development. This article reviews the aetiology, pathogenesis, and pathology of cervical neoplasia, emphasising the role of HPVs. (J Clin Pathol 1998;51:96-103) Keywords: human papillomavirus; cervical neoplasia This review is based on three presentations by the authors to the first National Cervical Screening Conference organised by Marie Curie Cancer Care and held in Oxford, UK in September 1996. It also includes several more recent developments. It is important to emphasise that the cervical screening programme aims to detect women who have an epithelial abnormality that might, if untreated, lead to the development of cervical carcinoma. The screening programme is not designed to detect small or early invasive carcinomas, but no screening system will detect all women at risk and it is inevitable that in a small prop...

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“…21 studies of GSTM1 polymorphisms (2,250 CC cases and 3,025 controls) [6,8,[10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] , 17 studies of GSTT1 polymorphisms (1,704 CC cases and 2,060 controls) genotypes [6, 11-13, 15-17, 20-24, 26-30] , and 9 studies of GSTM1-GSTT1 interaction analyses (1,046 CC cases and 1,319 controls) [6,11,12,15,16,24,26,28] were included in our meta-analysis. The characteristics of the studies are summarized in Table 1.…”

Section: Resultsmentioning

confidence: 99%

An Updated Meta-Analysis: Cervical Cancer Risk Conferred by GSTM1 and GSTT1 Polymorphisms

Liu¹,

Zeng²,

Ma³

et al. 2017

ijSciences

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Objective: To study the influence of GSTM1 and GSTT1 gene polymorphisms on cervical cancer (CC) risk, and explore genetic-environmental interactions. Methods: After a systematic literature search, all relevant studies entailing the association between GST polymorphisms and CC were included. The pooled odds ratio (OR) was used for analysis of the results and corresponding 95% confidence intervals (CI) were estimated. Results: A total of 23 case-control studies were included in the meta-analysis of GSTM1 (2,250 CC cases and 3,025 controls) and GSTT1 (1,704 CC cases and 2,460 controls) genotypes. For the GSTM1 polymorphisms, the null genotype of GSTM1 was associated with an increased CC risk for the total population (OR=1.57, 95% CI=1.25-1.98). A similar association was found in China (OR=2.34, 95% CI=1.56-3.52), India (OR=2.02, 95% CI=1.43-2.83), Pakistan (OR=5.52, 95% CI=2.34-13.07), Serbia (OR=1.73, 95% CI=0.68-4.39) and Kazakhstan (OR=6.5, 95%CI=2.25-18.81), but was not noted for others countries. Regarding human papilloma virus (HPV) infection, moderately but significantly increased risk of the null GSTM1 genotype was found in HPV-positive patients (OR=2.59, 95% CI=1.57-4.27). For the GSTT1 polymorphisms, the null GSTT1 genotype was associated with increased CC risk in the total population (OR=1.44, 95% CI=1.07-1.93). Regarding ethnic stratification, a significantly increased risk of the null GSTT1 genotype was found in Kazakhstan (OR=3.99, and Brazil (OR=4.58, 95% CI=2.04-10.28). With respect to smoking, the two aspects of the analysis above were not significantly associated with CC risk in smokers or non-smokers, respectively. For the GSTM1/GSTT1 interaction analysis, the dual null genotypes of GSTM1/GSTT1 were significantly associated with increased CC risk for the total population (OR=1.62, 95% CI=1.14-2.29). Conclusion: This meta-analysis provided sufficient evidence that the null genotype of GSTM1, or GSTT1 and the dual-null genotypes of GSTM1/GSTT1 are associated with CC.

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Progression of cervical intraepithelial neoplasia to cervical cancer: interactions of cytochrome P450 CYP2D6 EM and glutathione s-transferase GSTM1 null genotypes and cigarette smoking

Cited by 32 publications

References 20 publications

Co-fatores do HPV na oncogênese cervical

Co-fatores do HPV na oncogênese cervical

Aetiology, pathogenesis, and pathology of cervical neoplasia.

An Updated Meta-Analysis: Cervical Cancer Risk Conferred by GSTM1 and GSTT1 Polymorphisms

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