Lesão de DNA e Reparação

O nosso grupo estuda essencialmente mecanismos moleculares da carcinogénese, especialmente relacionados com as vias de reparação do DNA, estudando como a perfil genético pode influenciar o papel da lesão de DNA e a suscetibilidade genética em patologias crónicas como o cancro de mama e tiroide. 

Tendo por base a biologia molecular da doença e novas metodologias (por exemplo, tecnologias de sequenciamento e ferramentas de edição de genoma), o nosso foco é avaliar as variantes genéticas e correlacioná-las com a ocorrência e progressão da doença. Muitas dessas abordagens podem ser relevantes para identificar potenciais biomarcadores de doenças e alvos terapêuticos, bem como classificar o papel biológico de variantes genéticas identificadas em exames clínicos envolvendo metodologias de sequenciamento maciço. Para tal, utilizamos modelos in vitro, mas também amostras humanas, destacando que a investigação translacional entre a compreensão genética e a clínica é fundamental.

Graphical Abstract
  • Terry Fox Grant 2017. Liga Portuguesa Contra o Cancro. “Breast Cancer: clinical significance of variants of unknown significance (VUSs) in homologous recombination repair genes – from sequencing to functional analysis in familial breast cancer patients”, PI Susana Nunes Silva, April 2017.
    The aim of this study is to perform a functional analysis in vitro in peripheral lymphocytes of breast cancer patients and their unaffected relatives who have been previously sequenced for BRCA1 and BRCA2 genes and found to have Variants of Unknown Significance (VUS), through the assessment of cellular response to a genotoxic challenge induced by chemical agents and -radiation. The preliminary results in human samples, allowed the establishment of a cellular model using cell lines in which CRISPR-Cas9 system is used as genome editing tool to study additional variants in a breast cell line, and then functional assays are being performed in order to determine the impact of genetic variants in other high penetrant genes, particularly their role in DNA damage response.
    This project was developed in collaboration with José Pereira Leal of Ophiomics (expertise in sequencing), and Octávia Monteiro Gil from IST (expertise in genotoxic challenges and radiation).
  • Funding for ToxOmics from FCT: UIDB/00009/2020 (93121007) and UIDP/00009/2020 (93121008).
  • Terry Fox Grant 2017. Liga Portuguesa Contra o Cancro. “Breast Cancer: clinical significance of variants of unknown significance (VUSs) in homologous recombination repair genes – from sequencing to functional analysis in familial breast cancer patients”, PI Susana Nunes Silva, April 2017.
  •  “The usefulness of serologic infection markers in Pneumocystis jirovecii pneumonia (PcP): A new diagnostic approach.” CMDT-LA, PI Francisco Esteves, IHMT-UNL, January-December 2012.
  •  “Clinical relevance of multiple genetic markers in Pneumocystis jirovecii pneumonia (PcP): New high-throughput methodologies for molecular epidemiology and diagnosis.” PTDC/SAU-MIC/116716/2010. PI: Olga Matos, IHMT-UNL. Started in January 2010.
  • “GenFA – Occupational Exposure to Formaldehyde. Genotoxic Damage and Susceptibility evaluation in Pathology Anatomy Laboratory workers”. PTDC/SAU-ESA/102367/2008. PI: João Paulo Teixeira, INSA. Started: April 2010.
  • “The Role of β-glucan in Pneumocystis jiroverii Pneumonia (PcP): A new diagnostic tool.” PTDC/SAU-MII/104231/2008. PI: Olga Matos, IHMT-UNL. Started: January 2010.
  • “Biomarkers of dietary acrylamide exposure: human toxicological relevance”. PTDC/SAU-OSM/105572/2008. 
  • “Detection of DNA adducts in populations exposed to environmental carcinogens using colloidal gold nanoprobes” Fundação Calouste Gulbenkian. Projeto nº 76436, April 2006 – March 2009.
  • “Acrylamide-induced genetic damage: What is its relevance in breast, thyroid and central nervous system carcinogenesis?”Fundação Calouste Gulbenkian. Projeto nº 76438, February 2006 - January 2009.
  • “Breast cancer Genetic Susceptibility”. Fundação Calouste Gulbenkian. Projeto nº 69405, December 2004 a November2007.
  • “Identification of risk factors for primary central nervous system tumors”. Fundação Calouste Gulbenkian. Projeto nº 69407, December 2004 a November 2007.

Silva SN, Gomes BC, André S, Félix A, Rodrigues AS, Rueff J., Male and female breast cancer: the two faces of the same genetic susceptibility coin. Breast Cancer Res Treat. 2021 Jul;188(1):295-305. doi: 10.1007/s10549-021-06159-x. 

S Santos L, M Gil O, N Silva S, C Gomes B, C Ferreira T, Limbert E, Rueff J., Micronuclei Formation upon Radioiodine Therapy for Well-Differentiated Thyroid Cancer: The Influence of DNA Repair Genes Variants. Genes (Basel). 2020 Sep 17;11(9):1083. doi:10.3390/genes11091083.

Brás A, Rodrigues AS, Rueff J., Copy number variations and constitutional chromothripsis (Review). Biomed Rep. 2020 Sep;13(3):11. doi: 10.3892/br.2020.1318. 

Santos LS, Gomes BC, Bastos HN, Gil OM, Azevedo AP, Ferreira TC, Limbert E, Silva SN, Rueff J. Thyroid Cancer: The Quest for Genetic Susceptibility Involving DNA Repair Genes. Genes (Basel). 2019 Aug 1;10(8):586. doi: 10.3390/genes10080586.

Azevedo AP, Silva SN, Reichert A, Lima F, Júnior E, Rueff J., Effects of polymorphic DNA genes involved in BER and caspase pathways on the clinical outcome of myeloproliferative neoplasms under treatment with hydroxyurea. Mol Med Rep. 2018 Dec;18(6):5243-5255. doi: 10.3892/mmr.2018.9535. 

Santos LS, Silva SN, Gil OM, Ferreira TC, Limbert E, Rueff J., Mismatch repair single nucleotide polymorphisms and thyroid cancer susceptibility. Oncol Lett. 2018 May;15(5):6715-6726. doi: 10.3892/ol.2018.8103. 

Azevedo AP, Silva SN, Reichert A, Lima F, Júnior E, Rueff J., The Role of Caspase Genes Polymorphisms in Genetic Susceptibility to Philadelphia-Negative Myeloproliferative Neoplasms in a Portuguese Population. Pathol Oncol Res. 2019 Jul;25(3):961-969. doi: 10.1007/s12253-018-0411-y. 

Brás A, Rodrigues AS, Gomes B, Rueff J., Down syndrome and microRNAs. Biomed Rep. 2018 Jan;8(1):11-16. doi: 10.3892/br.2017.1019. 

Azevedo AP, Silva SN, Reichert A, Lima F, Júnior E, Rueff J., Prevalence of the Janus kinase 2 V617F mutation in Philadelphia-negative myeloproliferative neoplasms in a Portuguese population. Biomed Rep. 2017 Oct;7(4):370-376. doi: 10.3892/br.2017.977. 

Azevedo AP, Silva SN, De Lima JP, Reichert A, Lima F, Júnior E, Rueff J., DNA repair genes polymorphisms and genetic susceptibility to Philadelphia-negative myeloproliferative neoplasms in a Portuguese population: The role of base excision repair genes polymorphisms. Oncol Lett. 2017 Jun;13(6):4641-4650. doi: 10.3892/ol.2017.6065. 

Dʼ Oliveira Martins F, Gomes BC, Rodrigues AS, Rueff J., Genetic Susceptibility in Acute Pancreatitis: Genotyping of GSTM1, GSTT1, GSTP1, CASP7, CASP8, CASP9, CASP10, LTA, TNFRSF1B, and TP53 Gene Variants. Pancreas. 2017 Jan;46(1):71-76. doi: 10.1097/MPA.0000000000000707.

  • Ana Félix, MD, PhD - IPO Lisboa
  • Guilherme Bezerra de Castro, MD, PhD, Molecular Cancer Research Center
  • Nuno Guerreiro Oliveira, PhD - FF-UL
  • Octávia Monteiro Gil, PhD - Centro de Ciências e Tecnologias Nucleares, IST-UL.
  • Saudade André, PhD - IPO Lisboa

Investigador Principal

Susana Nunes Silva

Equipa

Ana Paula Azevedo
Medical Researcher
Cristina Caroça
Helena Borba
Researcher
Matilde Vale
Master Student
Rita Marrazes
Master Student
Susana Nunes Silva