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CHRNA5’s genetic and epigenetic contributions to the development of gynaecological tumours
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Resumo(s)
Os leiomiomas uterinos são tumores benignos monoclonais que se desenvolvem principalmente dentro da camada muscular lisa do útero e são altamente sensíveis às hormonas sexuais. Os leiomiomas podem aparecer em nódulos únicos ou múltiplos numa grande variedade de tamanhos e são classificados de acordo com a sua localização no útero. Dada a sua elevada dependência das hormonas sexuais, ocorrem sobretudo após a menarca e geralmente regridem após a menopausa. Estes tipos de tumores benignos são tipicamente assintomáticos, com apenas 30% das mulheres a apresentarem sintomas prejudiciais à qualidade de vida associados à pressão pélvica e/ou obstrução. O carcinoma cervical é um tumor maligno no revestimento do colo do útero causado por uma infeção persistente de um papilomavírus humano de alto risco (hrHPV). Esta é a infeção sexualmente transmissível mais comum no mundo, o que faz com que o carcinoma cervical seja um dos cinco cancros mais comuns nas mulheres, com cerca de 311 mil mortes anuais. Doentes com carcinomas maiores apresentam sintomas relacionados com pressão e/ou obstrução. O carcinoma cervical é uma doença altamente evitável através de métodos de prevenção como a vacinação contra o HPV e de programas de rastreio que permitem a sua deteção precoce. Neste projeto, estudos genéticos permitiram a associação do risco de desenvolvimento das doenças acima mencionadas com o polimorfismo rs16969968 do gene CHRNA5. Este gene codifica uma subunidade do recetor colinérgico nicotínico alfa 5 necessária para a formação de um recetor nicotínico acetilcolina. Os recetores nicotínicos de acetilcolina são recetores transmembranares envolvidos em respostas biológicas como a proliferação celular e a angiogénese, quando ativados pela nicotina ou pela acetilcolina. Os resultados mostraram um efeito protetor do genótipo menos frequente (AA) sobre o desenvolvimento de leiomiomas, apesar de estudos realizados noutros laboratórios tenham associado o polimorfismo rs16969968 à dependência da nicotina e ao desenvolvimento do cancro do pulmão. No mesmo sentido, o genótipo GG foi reconhecido como um fator de risco tanto para o desenvolvimento de leiomiomas como de carcinoma do colo do útero ou lesões precursoras. O genótipo GG também mostrou um efeito prejudicial em parâmetros clínicos como o número de leiomiomas desenvolvidos ou a diferença de volume do leiomioma principal após tratamento por embolização da artéria uterina. O genótipo AA contribuiu para um menor número de leiomiomas desenvolvidos e o genótipo AG para os maiores valores de redução do leiomioma principal após embolização da artéria uterina. Foram também realizados estudos genéticos com os genótipos epistáticos de CHRNA5 e genes que também participam na sinalização celular e respostas biológicas, previamente estudados no Instituto Bento da Rocha Cabral (ADRB2, SLC6A4 e HTR2A). Não foi possível estabelecer uma associação entre nenhum dos genótipos epistáticos e o desenvolvimento de leiomiomas. No entanto, os genótipos epistáticos entre CHRNA5 e SLC6A4, e CHRNA5 e HTR2A afetaram significativamente o número de leiomiomas desenvolvidos. O volume do leiomioma principal após embolização da artéria uterina também foi influenciado por um único genótipo epistático dos genes CHRNA5 e SLC6A4. Este resultado revelou um efeito sinergético entre estes dois genes, uma vez que o valor de redução era mais elevado para o genótipo epistático do que para cada um dos genótipos em particular. Um único genótipo epistático com os genes CHRNA5 e SLC6A4 influenciou significativamente o desenvolvimento de carcinoma cervical ou lesões precursoras. Neste estudo, foi revelado um aumento do efeito de risco deste genótipo epistático, quando comparado com cada genótipo separadamente, visto que o risco de desenvolvimento desta doença fornecido por esta epistasia proporcionava três vezes o risco proporcionado apenas pelo genótipo GG do gene CHRNA5. Também se previu um estudo epigenético com o objetivo de determinar se existiam alterações significativamente diferentes nos padrões de metilação do promotor do CHRNA5 entre as Populações Leiomioma e Controlo. No entanto, visto que os ensaios realizados basearam-se numa razão metilado/não metilado entre duas amostras (controlo/doença), não foi possível determinar nenhuma conclusão, já que os resultados obtidos mas não foram claros relativamente ao promotor quando não metilado.
Uterine leiomyomas are monoclonal benign tumours that develop primarily within the smooth muscular layer of the uterus and are highly responsive to sexual hormones. Leiomyomas may appear in single or multiple nodules in a large array of sizes and are classified according to their location in the uterus. Given their high dependency on sexual hormones, they occur mostly after menarche and generally regress after menopause. These types of benign tumours are typically asymptomatic, with only 30% of women presenting life quality damaging symptoms associated with pelvic pressure and/or obstruction. Cervical carcinoma is a malignant tumour in the lining of the cervix caused by a persistent infection of a high-risk Human Papillomavirus (hrHPV). This infection is the most common sexual transmitted infection (STI) in the world, making cervical carcinoma in the top five most common cancers in women leading to 311 thousand death each year. Patients with larger carcinomas present symptoms related to pressure and/or obstruction. Cervical carcinoma is a highly preventable disease through vaccination against HPV and screening programs which allow for early detection. In this project, genetic studies allowed the association of the risk of developing the aforementioned diseases with the polymorphism rs16969968 of the CHRNA5 gene. This gene encodes for a cholinergic receptor nicotinic alpha 5 subunit necessary for the formation of a nicotinic acetylcholine receptor. Nicotinic acetylcholine receptor are transmembrane receptors involved in biological responses like cellular proliferation and angiogenesis when activated by nicotine or acetylcholine. Results showed a protective effect of the AA genotype over leiomyoma development, even though the polymorphism rs16969968 has been reported in other studies to be associated with nicotine dependence and lung cancer development. Also, the GG genotype was identified as a risk factor both on leiomyoma and cervical carcinoma or precursor lesions development. The GG genotype also displayed a harming effect over clinical parameters like the number of leiomyomas developed or the difference of volume of the main leiomyoma after treatment by uterine artery embolization. Whereas AA genotype contributed for a lower number of leiomyomas developed and AG genotype for the highest values of reduction of the main leiomyoma after uterine artery embolization. Genetic studies were also made to epistatic genotypes of CHRNA5 and genes who also participate in cellular signalling and biological responses, previously studied in Instituto Bento da Rocha Cabral (ADRB2, SLC6A4 and HTR2A). It was not possible to establish an association between any of the epistatic genotypes and the development of leiomyomas. However, epistatic genotypes between CHRNA5 and SLC6A4, and CHRNA5 and HTR2A significantly affected the number of leiomyomas developed. The volume of the main leiomyoma after uterine artery embolization was also influenced by a single epistatic genotype from CHRNA5 and SLC6A4 genes. This result uncovered a synergetic effect between these two genes since the reduction value was higher for the epistatic genotype than for the genotypes in particular. A single epistatic genotype involving CHRNA5 and SLC6A4 genes greatly influenced the development of cervical carcinoma or precursor lesions. In this study, it was revealed na increased harmful effect of this epistatic genotype, once compared with each single genotypes separately, since the risk of development of this disease provided by this epistasis was threefold the risk provided by the GG genotype from the CHRNA5 gene alone. An epigenetic study was also planned in order to infer if there were significantly different changes in the methylation patterns of CHRNA5’s promotor between Leiomyoma and Control Population. However, results from these experiments could not lead to conclusions since assays were based in a methylated/unmethylated ratio between two samples (control/disease), but no clear data was obtained concerning the unmethylated promoter.
Uterine leiomyomas are monoclonal benign tumours that develop primarily within the smooth muscular layer of the uterus and are highly responsive to sexual hormones. Leiomyomas may appear in single or multiple nodules in a large array of sizes and are classified according to their location in the uterus. Given their high dependency on sexual hormones, they occur mostly after menarche and generally regress after menopause. These types of benign tumours are typically asymptomatic, with only 30% of women presenting life quality damaging symptoms associated with pelvic pressure and/or obstruction. Cervical carcinoma is a malignant tumour in the lining of the cervix caused by a persistent infection of a high-risk Human Papillomavirus (hrHPV). This infection is the most common sexual transmitted infection (STI) in the world, making cervical carcinoma in the top five most common cancers in women leading to 311 thousand death each year. Patients with larger carcinomas present symptoms related to pressure and/or obstruction. Cervical carcinoma is a highly preventable disease through vaccination against HPV and screening programs which allow for early detection. In this project, genetic studies allowed the association of the risk of developing the aforementioned diseases with the polymorphism rs16969968 of the CHRNA5 gene. This gene encodes for a cholinergic receptor nicotinic alpha 5 subunit necessary for the formation of a nicotinic acetylcholine receptor. Nicotinic acetylcholine receptor are transmembrane receptors involved in biological responses like cellular proliferation and angiogenesis when activated by nicotine or acetylcholine. Results showed a protective effect of the AA genotype over leiomyoma development, even though the polymorphism rs16969968 has been reported in other studies to be associated with nicotine dependence and lung cancer development. Also, the GG genotype was identified as a risk factor both on leiomyoma and cervical carcinoma or precursor lesions development. The GG genotype also displayed a harming effect over clinical parameters like the number of leiomyomas developed or the difference of volume of the main leiomyoma after treatment by uterine artery embolization. Whereas AA genotype contributed for a lower number of leiomyomas developed and AG genotype for the highest values of reduction of the main leiomyoma after uterine artery embolization. Genetic studies were also made to epistatic genotypes of CHRNA5 and genes who also participate in cellular signalling and biological responses, previously studied in Instituto Bento da Rocha Cabral (ADRB2, SLC6A4 and HTR2A). It was not possible to establish an association between any of the epistatic genotypes and the development of leiomyomas. However, epistatic genotypes between CHRNA5 and SLC6A4, and CHRNA5 and HTR2A significantly affected the number of leiomyomas developed. The volume of the main leiomyoma after uterine artery embolization was also influenced by a single epistatic genotype from CHRNA5 and SLC6A4 genes. This result uncovered a synergetic effect between these two genes since the reduction value was higher for the epistatic genotype than for the genotypes in particular. A single epistatic genotype involving CHRNA5 and SLC6A4 genes greatly influenced the development of cervical carcinoma or precursor lesions. In this study, it was revealed na increased harmful effect of this epistatic genotype, once compared with each single genotypes separately, since the risk of development of this disease provided by this epistasis was threefold the risk provided by the GG genotype from the CHRNA5 gene alone. An epigenetic study was also planned in order to infer if there were significantly different changes in the methylation patterns of CHRNA5’s promotor between Leiomyoma and Control Population. However, results from these experiments could not lead to conclusions since assays were based in a methylated/unmethylated ratio between two samples (control/disease), but no clear data was obtained concerning the unmethylated promoter.
Descrição
Tese de mestrado em Biologia Humana e Ambiente, Universidade de Lisboa, Faculdade de Ciências, 2021
Palavras-chave
Leiomioma Carcinoma cervical CHRNA5 Epistasia Teses de mestrado - 2021