Oncogenética (GOG)

Somos um grupo multidisciplinar focado na caracterização de padrões de alterações genéticas potencialmente envolvidos no surgimento do cancro, bem como na compreensão dos mecanismos de progressão tumoral e resposta à terapêutica. Adicionalmente, estudamos variantes genéticas hereditárias associadas à predisposição para cancro, assim como de padrões de alterações genéticas somáticas que ocorrem em síndromes hereditários de cancro. Com vista à formulação de terapias especificas dirigidas às alterações metabólicas do tumor, o conhecimento aprofundado das alterações somáticas ou adquiridas de cada indivíduo é, atualmente, decisivo na escolha da abordagem terapêutica mais adequada.

 

COORDENADOR CIENTÍFICO

Manuel António Rodrigues Teixeira, MD, PhD
ORCID ID: 0000-0002-4896-5982
Investigador coordenador
Diretor do Serviço de Genética Laboratorial do IPO Porto;
Professor Catedrático Convidado no ICBAS da Universidade do Porto
E-mail: manuel.teixeira@ipoporto.min-saude.pt

EQUIPA
Investigadores Auxiliares

Paula Cristina Martins Paulo, PhD
ORCID ID: 0000-0001-8387-2127
E-mail: paula.paulo@ipoporto.min-saude.pt

Manuela Pinheiro, PhD
ORCID ID: 0000-0001-8228-3435
E-mail: manuelap@ipoporto.min-saude.pt

 

Investigadores Júnior

Andreia Brandão, PhD
ORCID ID: 0000-0003-0938-1543
andreia.aguiar.brandao@ipoporto.min-saude.pt

Luísa Ferreira, PhD
ORCID ID: 0000-0002-0868-3964
a.t.ferreira@ipoporto.min-saude.pt

 

Assistentes de Investigação

Patrícia Arinto, MSc, IPOP; E-mail: i12821@ipoporto.min-saude.pt
Adriana Resende, MSc, IPOP; E-mail: i12822@ipoporto.min-saude.pt
Miguel Porto Silva, MSc, IPOP; E-mail: i12859@ipoporto.min-saude.pt

 

Doutorandos

Marta Cardoso, MSc, ICBAS/IPOP; E-mail: marta.jose.cardoso@ipoporto.min-saude.pt
Maria Pedro da Silva, MSc, ICBAS/IPOP; E-mail: maria.pereira.silva@ipoporto.min-saude.pt
Joana Sofia Gonçalves Guerra, MSc, ICBAS/IPOP; E-mail: joana.goncalves.guerra@ipoporto.min-saude.pt
Pedro Emanuel Gomes, BSc, FPCE/IPOP; E-mail: pedro.silva.gomes@ipoporto.min-saude.pt

 

Mestrandos

Marta Loureiro, BSc, ICBAS; up202002997@edu.icbas.up.pt

 

Outros Membros (parcial)

Ana Barbosa, PhD, Serviço de Genética Laboratorial, IPO Porto
Ana Peixoto, PhD, Serviço de Genética Laboratorial, IPO Porto
Carla Escudeiro, MSc, Serviço de Genética Laboratorial, IPO Porto
Carla Pinto, MSc, Serviço de Genética Laboratorial, IPO Porto
Catarina Santos, MSc, Serviço de Genética Laboratorial, IPO Porto
Cecília Correia, MSc, Serviço de Genética Laboratorial, IPO Porto
Isabel Veiga, MSc, Serviço de Genética Laboratorial, IPO Porto
Joana Vieira, MSc, Serviço de Genética Laboratorial, IPO Porto
Lurdes Torres, MSc, Serviço de Genética Laboratorial, IPO Porto
Patrícia Rocha, MSc, Serviço de Genética Laboratorial, IPO Porto
Susana Bizarro, MSc, Serviço de Genética Laboratorial, IPO Porto
Susana Lisboa, MSc, Serviço de Genética Laboratorial, IPO Porto
João Silva, MD, Serviço de Genética Médica, IPO Porto
Sara Ribeiro, MD, Serviço de Genética Médica, IPO Porto
Eunice Silva, PhD, Serviço de Psicologia médica, IPO Porto
Sofia Maia, MD, PhD, Serviço de Genética médica, CHUC
Raquel Martins, MD, PhD, Serviço de Endocrinologia, IPO Coimbra

OBJETIVOS 

Uma das linhas principais de investigação envolve a caracterização das causas genéticas de predisposição para cancro de próstata (CaP) hereditário, visando identificar, pelo menos, parte da heritabilidade desconhecida. Uma segunda grande linha investigação o uso de células tumorais livres em circulação (circulating cell-free tumor DNA – ctDNA) com vista à sua aplicação no diagnóstico molecular, testes preditivos de resposta à terapêutica e screening oncológico. Esta estratégica tem sido implementada como método de monitorização de resposta e de estudo de mecanismos de resistência à terapia e serão testados em portadores de alto risco membros de famílias com síndromes de cancro hereditário.

PROJETOS COM FINANCIAMENTO EXTERNO

 

  • TOGETHER (PTDC/PSI-ESP/30980/2017): Connecting people and systems to support an effective psychosocial adjustment to genetic testing in the context of inherited cancer risk (01/07/2018-30/06/2022); Eunice Silva.

 

  • LUNG-ctDNA (CI-IPOP-126-2019): Characterization of targeted therapy resistance mechanisms in EGFR/ALK/ROS1/BRAF-positive NSCLC by gene panel NGS in circulating cell-free DNA (01/09/2021-31/12/2023); Manuel Teixeira.

 

PROJETOS COM FINANCIAMENTO INTERNO

• HPC (CI-IPOP-24-2015): Inherited predisposition to prostate cancer (01/10/2011-31/12/2024); Manuel Teixeira.
• ctDNA-BRCA (CI-IPOP-35-2016): Identification of somatic and germline mutations in circulating tumor DNA in ovarian cancer patients and in germline BRCA1/BRCA2 mutation carriers undergoing cancer screening (01/05/2016-31/12/2024); Ana Barbosa & Manuel Teixeira.
• ctDNA-Lynch (CI-IPOP-36-2016): Detection of cancer specific genetic alterations in circulating free tumor DNA as a tool for early cancer diagnosis and follow up in Lynch syndrome patients (01/09/2016-31/12/2024); Manuela Pinheiro & Manuel Teixeira.
• ctDNA-Cancer (CI-IPOP-54-2017): Validation of liquid biopsies for predictive biomarker testing, therapy response monitoring, and resistance mechanism identification in cancer patients (01/09/2017-31/12/2024); Manuel Teixeira.
• CaGaGen (CI-IPOP-56-2017): Identification of germline mutations by gene-panel next generation sequencing in familial tubular and mixed tubular-diffuse gastric cancer (01/09/2018-31/12/2023); Joana Guerra & Manuel Teixeira.
• STOP-TKI (CI-IPOP-120-2019): The role of immune system for treatment-free remission in CML patients who stopped TKI therapy (01/09/2019-31/12/2023); Manuel Teixeira.
• VATER (CI-IPOP-128-2020): Landscape of somatic and germline genetic alterations in ampullary carcinomas (01/09/2019-31/12/2023); Inês Ribas & Manuel Teixeira.
• MetPC (CI-IPOP-129-2020): Simultaneous detection of germline and somatic mutations in DNA repair genes by next generation sequencing of tumor samples and cell-free DNA from metastatic prostate cancer patients (01/04/2021-31/12/2024); Manuel Teixeira.
• PATHSEARCH (CI-IPOP-154-2021): Understanding the polygenic basis of hereditary predisposition to prostate cancer: a multi-omics integrative approach combining genomics and transcriptomics (16/05/2022-15/05/2028); Andreia Brandão & Manuel Teixeira.
• TREATCILIA (CI-IPOP-155-2021): Theragnostic exploitation of ciliogenesis defects in prostate cancer (01/06/2022-31/12/2025); Paula Paulo & Manuel Teixeira.
• POLYRISK (CI-IPOP-156-2021): Impacto da sequenciação de nova geração multigénica e do score de risco poligénico na predisposição hereditária para cancro da mama (01/04/2022-31/12/2022); Marta Loureiro & Manuel Teixeira.

PUBLICAÇÕES SELECIONADAS 

 

Gene panel tumor testing in ovarian cancer patients significantly increases the yield of clinically actionable germline variants beyond BRCA1/BRCA2.
In this study, we aimed to evaluate the yield of clinically actionable germline variants using next-generation sequencing of a customized panel of 10 genes for the analysis of formalin-fixed paraffin-embedded samples from 96 ovarian carcinomas, a strategy that allows the detection of both somatic and germline variants in a single test. In addition to 13.7% of deleterious germline BRCA1/BRCA2 carriers, we identified 7.4% additional patients with pathogenic germline variants in other genes predisposing for ovarian cancer, namely RAD51C, RAD51D, and MSH6, representing 35% of all pathogenic germline variants. We conclude that the strategy of reflex gene-panel tumor testing enables the identification of clinically actionable germline variants in a significantly higher proportion of ovarian cancer patients, which may be valuable information in patients with advanced disease that have run out of approved therapeutic options. Furthermore, this approach increases the chance to make available genetic counseling, presymptomatic genetic testing, and gynecological cancer prophylaxis to female relatives who turn out to be healthy carriers of deleterious germline variants. (Cancers 2020, 12(10):2834. Impact factor: 6.126).

The CHEK2 variant c.349A>G is associated with prostate cancer risk and carriers share a common ancestor.
In this study, we evaluated the prevalence and relative risk of the CHEK2 recurrent variant c.349A>G in a series of 462 Portuguese patients with early-onset and/or familial/hereditary prostate cancer (PrCa), as well as in the large multicentre PRACTICAL case-control study comprising 55,162 prostate cancer cases and 36,147 controls. Additionally, we investigated the potential shared ancestry of the carriers by performing identity-by-descent, haplotype and age estimation analyses using high-density SNP data from 70 variant carriers belonging to 11 different populations included in the PRACTICAL consortium. The CHEK2 missense variant c.349A>G was found significantly associated with an increased risk for PrCa (OR 1.9; 95% CI: 1.1-3.2). A shared haplotype flanking the variant in all carriers was identified, strongly suggesting a common founder of European origin. Additionally, using two independent statistical algorithms, implemented by DMLE+2.3 and ESTIAGE, we were able to estimate the age of the variant between 2300 and 3125 years. By extending the haplotype analysis to 14 additional carrier families, a shared core haplotype was revealed among all carriers matching the conserved region previously identified in the high-density SNP analysis. These findings are consistent with CHEK2 c.349A>G being a founder variant associated with increased PrCa risk, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families. (Cancers 2020, 12(11):3254. Impact factor: 6.126).

Tumor testing for somatic and germline BRCA1/BRCA2 variants in ovarian cancer patients in the context of strong founder effects.
BRCA1/BRCA2 tumor testing by next-generation sequencing (NGS) can detect simultaneously both somatic and germline variants, allowing the identification of more patients with higher likelihood of benefiting from PARPi. Our main goal was to determine the frequency of somatic and germline BRCA1/BRCA2 variants in a series of non-mucinous OC, and to define the best strategy to be implemented in a routine diagnostic setting for the screening of germline/somatic variants in these genes, including the BRCA2 c.156_157insAlu Portuguese founder variant. We observed a frequency of 19.3% of deleterious variants, 13.3% germline, and 5.9% somatic. A higher prevalence of pathogenic variants was observed in patients diagnosed with high-grade serous ovarian cancer (23.2%). Considering the frequencies of the c.3331_3334del and the c.2037delinsCC BRCA1 variants observed in this study (73% of all BRCA1 pathogenic germline variants identified) and the limitations of NGS to detect the BRCA2 c.156_157insAlu variant, it might be cost-effective to test for these founder variants with a specific test prior to tumor screening of the entire coding regions of BRCA1 and BRCA2 by NGS in patients of Portuguese ancestry (Front Oncol 2020, 10:1318. Impact factor: 4.848).

The role of TP53 pathogenic variants in early-onset HER2-positive breast cancer.
In this study, we assessed the prevalence of germline TP53 variants by Sanger sequencing or next-generation sequencing in 149 women with HER2-positive breast cancer diagnosed until age 40. The pattern of HER2 amplification was evaluated with dual-probe FISH in a subset of breast carcinomas from patients with germline TP53 variants as compared with those of noncarriers. Among 149 women tested, three presented a deleterious TP53 germline variant (2%), with one patient diagnosed at age 31 and the other two with bilateral breast cancer at ages 29/33 and 28/32, respectively. Three of the 36 patients (8.3%) with the first breast cancer diagnosed at age 31 or younger presented a pathogenic TP53 variant. Additionally, all TP53 deleterious variant carriers had a first degree relative diagnosed with different early-onset cancers (frequently not belonging to the Li-Fraumeni syndrome tumor spectrum) diagnosed at age 45 or younger. Higher levels of HER2 amplification were found in breast carcinomas of TP53 pathogenic variant carriers than in those of noncarriers. Deleterious germline TP53 variants account for a small proportion of early-onset HER2-positive breast cancers, but these seem to have higher HER2 amplification ratios. All TP53 pathogenic variant carriers found in this study had the first breast carcinoma diagnosed at age 31 or younger and a first-degree relative with early-onset cancer. Further studies are needed to clarify if HER2 status in early-onset breast cancer patients, in combination with other personal and/or familial cancer history, is useful to update the TP53 testing criteria. (Fam Cancer 2021, 20(3):173-180. Impact factor: 2.375).

Next generation sequencing of tumor and matched plasma samples: Identification of somatic variants in ctDNA from ovarian cancer patients.
In this study, using a custom panel of 27 genes, next-generation sequencing (NGS) was performed on tumor and matched plasma samples from 96 OC patients, which were combined in two groups (treatment naive and post-treatment). Overall, at least one somatic variant present in the tumor sample was also detected in the matched plasma sample in 35.6% of the patients, a percentage that increased to 69.6% of the treatment naive patients and 83.3% of those with stage IV disease, showing the potential of ctDNA analysis as an alternative to identify somatic variants in these patients, namely those that have predictive value for targeted therapy. In fact, of the two treatment-naive patients with somatic BRCA1 variants identified in tumor samples, in one of them we detected in ctDNA a BRCA1 somatic variant that was present in the tumor with a VAF of 53%, but not in the one that had a VAF of 5.4%. We also showed that ctDNA analysis has a complementary role to molecular unraveling of inter- and intra-tumor heterogeneity, as exemplified by one patient diagnosed with bilateral OC in which different somatic variants from both tumors were detected in ctDNA. Interestingly, as these bilateral tumors shared a rare combination of two of the three variants identified in ctDNA, we could conclude that these morphologically different tumors were clonally related and not synchronous independent neoplasias. Moreover, in the post-treatment group of patients with plasma samples collected after surgery, those with detectable somatic variants had poor prognosis when compared with patients with no detectable somatic variants, highlighting the potential of ctDNA analysis to identify patients at higher risk of recurrence. Concluding, this study demonstrated that somatic variants can be detected in plasma samples of a significant proportion of OC patients, supporting the use of NGS-based ctDNA testing for noninvasive tumor molecular profiling and to stratify patients according to prognosis. (Front Oncol 2021, 11:754094. Impact factor: 6.244).

COLABORAÇÕES NACIONAIS

Nome PI: José Bessa
Instituição: i3S

Nome PI: Joana Paredes
Instituição: i3S

Nome PI: Hélder Maiato
Instituição: i3S

Nome PI: Carla Oliveira
Instituição: i3S

Nome PI: Raquel Seruca / José Carlos Machado
Instituição: i3S

COLABORAÇÕES INTERNACIONAIS

Nome PI: Rosalind Eeles, Zsofia Kote-Jarai
Instituição: Institute of Cancer Research
País: UK

Nome PI: Luis G Carvajal-Carmona
Instituição: UC Davis Genome Center
País: USA

Consortia membership: CIMBA, BCAC; PRACTICAL; ENIGMA; MERGE

 

*A informação descrita no grupo é da inteira responsabilidade do respectivo coordenador. 

 

equipa

contactos

telefone
225084000 (Ext: 7916)
email
localização
CI-LAB1, Edifício E, 6º Piso