Molecular characterization of novel candidate genes involved in the initiation of multiple primary melanomas

Detalhes bibliográficos
Autor(a) principal: Campos, Catarina Paula Abreu
Data de Publicação: 2019
Tipo de documento: Dissertação
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10451/38320
Resumo: Tese de mestrado, Biologia Molecular e Genética, Universidade de Lisboa, Faculdade de Ciências, 2019
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spelling Molecular characterization of novel candidate genes involved in the initiation of multiple primary melanomasMelanoma cutâneoMelanomas múltiplos primários (MMPs)Genes de suscetibilidadeSequenciação do exomaAnálise bioinformáticaTeses de mestrado - 2019Departamento de Biologia VegetalTese de mestrado, Biologia Molecular e Genética, Universidade de Lisboa, Faculdade de Ciências, 2019Cutaneous melanoma is considered one of the most aggressive human cancers due to its high invasive capacity. Several risk factors influence the development of melanoma, from which a genetic background is included. Approximately 5-12% of melanomas are familial cases, which comprise a higher frequency of multiple primary melanomas (MPMs). Approximately 20-40% of familial cases occur due to mutations in CDKN2A, a high-risk gene for cutaneous melanoma susceptibility. Other genes have also been described, although in a much lower percentage. Nevertheless, about 60-80% of all familial cases are caused by unknown genes. The aim of this study was the identification of novel susceptibility genes for MPMs. For this, whole exome sequencing was performed in 8 patients diagnosed with MPM, including two first-degree relatives, negative for germline mutations in the CDKN2A, CDK4 and MITF (p.E318K) genes. Afterwards, bioinformatics analysis, by the use of several criteria, allowed the identification of 19 variants potentially pathogenic, from which 5 were not validated as they were WES artefacts. Consequently, 13 variants were validated by the Sanger method: MAP2K3 (c.77G>C), MTCL1 (c.4315G>A), BMX (c.851C>T), NTN4 (c.1182C>T), FNDC1 (c.3332G>A), CDH23 (c.1096G>A), BRD9 (c.183G>C), CAND2 (c.992A>T), CFAP47 (c.4589A>C), ITIH3 (c.1130G>A), RNF213 (c.2122C>G), RPL32 (c.98G>A) and ARHGEF40 (c.2500C>T). Next, validated variants were screened, using the Sanger method, in 22 additional patients with MPM, 33 patients with familial melanoma and 100 healthy controls. Their association with MPM was calculated by the Fisher’s exact test, with an adjusted p-value using the BH method. In silico analysis was also performed for variant impact prediction using several tools, namely, SIFT, Polyphen-2, Provean, FATHMM, MutationTaster and Human Splicing Finder. A candidate gene literature search and gene analysis were also conducted for understanding the candidate genes function and possible relation to melanoma, respectively. Our results led to the identification of three potential mutations, specifically, CDH23 (c.1096G>A), BRD9 (c.183G>C) and ARHGEF40 (c.2500C>T), from which the BRD9 variant had a significant association with MPM. Furthermore, given their respective gene functions and prediction as damaging by several in silico tools, these appear to be promising pathogenic mutations. Several polymorphisms were also detected, therefore we hypothesized these might act together to increase melanoma susceptibility in a polygenic manner. However, functional studies should be conducted, to better understand the variants effect in normal and cancer cell lines and to evaluate their relevance in melanoma. In case of variant pathogenicity confirmation, the implementation of a NGS multigenic panel should also be considered in order to study the genes that harbor these variants as well as known susceptibility genes for melanoma.Pojo, MartaTrindade, Maria Helena Machado, 1963-Repositório da Universidade de LisboaCampos, Catarina Paula Abreu2022-03-20T01:30:33Z201920192019-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfhttp://hdl.handle.net/10451/38320TID:202231119enginfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-11-08T16:36:03Zoai:repositorio.ul.pt:10451/38320Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T21:52:09.931450Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Molecular characterization of novel candidate genes involved in the initiation of multiple primary melanomas
title Molecular characterization of novel candidate genes involved in the initiation of multiple primary melanomas
spellingShingle Molecular characterization of novel candidate genes involved in the initiation of multiple primary melanomas
Campos, Catarina Paula Abreu
Melanoma cutâneo
Melanomas múltiplos primários (MMPs)
Genes de suscetibilidade
Sequenciação do exoma
Análise bioinformática
Teses de mestrado - 2019
Departamento de Biologia Vegetal
title_short Molecular characterization of novel candidate genes involved in the initiation of multiple primary melanomas
title_full Molecular characterization of novel candidate genes involved in the initiation of multiple primary melanomas
title_fullStr Molecular characterization of novel candidate genes involved in the initiation of multiple primary melanomas
title_full_unstemmed Molecular characterization of novel candidate genes involved in the initiation of multiple primary melanomas
title_sort Molecular characterization of novel candidate genes involved in the initiation of multiple primary melanomas
author Campos, Catarina Paula Abreu
author_facet Campos, Catarina Paula Abreu
author_role author
dc.contributor.none.fl_str_mv Pojo, Marta
Trindade, Maria Helena Machado, 1963-
Repositório da Universidade de Lisboa
dc.contributor.author.fl_str_mv Campos, Catarina Paula Abreu
dc.subject.por.fl_str_mv Melanoma cutâneo
Melanomas múltiplos primários (MMPs)
Genes de suscetibilidade
Sequenciação do exoma
Análise bioinformática
Teses de mestrado - 2019
Departamento de Biologia Vegetal
topic Melanoma cutâneo
Melanomas múltiplos primários (MMPs)
Genes de suscetibilidade
Sequenciação do exoma
Análise bioinformática
Teses de mestrado - 2019
Departamento de Biologia Vegetal
description Tese de mestrado, Biologia Molecular e Genética, Universidade de Lisboa, Faculdade de Ciências, 2019
publishDate 2019
dc.date.none.fl_str_mv 2019
2019
2019-01-01T00:00:00Z
2022-03-20T01:30:33Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/masterThesis
format masterThesis
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10451/38320
TID:202231119
url http://hdl.handle.net/10451/38320
identifier_str_mv TID:202231119
dc.language.iso.fl_str_mv eng
language eng
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron:RCAAP
instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron_str RCAAP
institution RCAAP
reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
repository.mail.fl_str_mv
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