Cancer Genetics Group

The Cancer Genetics Group studies the interplay between inherited cancer predisposition and the pattern of acquired genetic alterations that give rise to cancer, in order to understand the mechanisms of tumor initiation and progression and their role in therapy response and resistance. In fact, the fields of germline and somatic genetics are progressively more interconnected, as exemplified by shared mutation signatures that might have similar predictive value for targeted cancer therapy. Several biologically and clinically relevant tumor models are studied, with emphasis in prostate cancer. It is a multidisciplinary research group that includes medical doctors, pharmacists, biochemists and biologists, all specialized in cancer genetics.

SCIENTIFIC COORDINATOR

Manuel R. Teixeira, MD, PhD
ORCID ID: 0000-0002-4896-5982
Group Coordinator/Senior Researcher (Research Coordinator)
Director of the Department of Laboratory Genetics of IPO Porto / Coordinator of the Cancer Genetics Group of CI-IPOP / Guest Full Professor (Medical Genetics and Cancer Genetics), School of Medicine and Biomedical Sciences (ICBAS), University of Porto
Email: manuel.teixeira@ipoporto.min-saude.pt

TEAM
SENIOR INVESTIGATORS

Paula Paulo, PhD
ORCID ID: 0000-0001-8387-2127
Senior Researcher (Assistant researcher)
Senior Researcher at the Cancer Genetics Group of CI-IPOP
Email: paula.paulo[at]ipoporto.min-saude.pt

JUNIOR RESEARCHERS

Andreia Brandão, PhD
ORCID ID: 0000-0003-0938-1543
PosDoc Researcher (Junior)
Junior researcher at the Cancer Genetics Group of CI-IPOP
E-mail: andreia.aguiar.brandao@ipoporto.min-saude.pt

Bernard Orr, PhD
ORCID ID: 0000-0002-9159-7644
PosDoc Researcher (Junior)
Junior researcher at the Cancer Genetics Group of CI-IPOP
E-mail: i13009@ipoporto.min-saude.pt

INVITED RESEARCHERS

Sofia Maia, MD, PhD
Ciência ID: 8713-CBDB-1CD0
Genetician
Coimbra University Hospital
E-mail: s.maia@chuc.min-saude.pt

PhD STUDENTS

Elsa Paiva, MSc (IPOP)
Ciência ID: 8214-06A6-66AB
E-mail: i36026@ipoporto.min-saude.pt

Pedro Gomes, MSc (IPOP/ FPCEUP)
Ciência ID: 1412-DEE3-E085
E-mail: pedro.silva.gomes@ipoporto.min-saude.pt

Rita Canário, MD (IPOP/i3S)
Ciência ID: 4D16-8D65-7129
E-mail: rita.canario@ipoporto.min-saude.pt

RESEARCH ASSISTANTS

Manuela Pinheiro, PhD
Ciência ID: 0216-6A5F-4983
E-mail: Manuela.Pinheiro[at]ipoporto.min-saude.pt

Cátia Gonçalves, MSc
Ciência ID: C01A-FB73-0A85
E-mail: catia.goncalves[at]ipoporto.min-saude.pt

MSc STUDENTS

Luca Rocha, BSc
Ciência ID: E411-0DDE-36D7
E-mail: luca.rocha[at]ipoporto.min-saude.pt

Madalena Ribeiro, Bsc
Ciência ID: F317-C67A-EDEE
E-mail: madalena.corado[at]ipoporto.min-saude.pt

Sofia Costa, BSc
Ciência ID: 0018-D631-03E9
E-mail: sofia.costa[at]ipoporto.min-saude.pt

OTHER COLLABORATORS

Ana Barbosa, PhD
Clinical Biologist
Ciência ID: E519-6872-5FE9

Ana Peixoto, PhD
Oncology Pharmacist
Ciência ID: 2014-3C52-DAC7

Adriana Resende, MSc
Clinical Biologist
Ciência ID: 2418-F824-8B08

Carla Pinto, MSc
Clinical Biologist
Ciência ID: 271F-E46E-86E8

Carla Escudeiro, MSc
Clinical Biologist
Ciência ID: B21B-3C92-5EB8

Catarina Santos, MSc
Clinical Biologist
Ciência ID: AC19-D7A8-6DE9

Cecília Correia, MSc
Clinical Biologist
Ciência ID: 0E10-1002-4547

Gabriela Soares, MD
Genetician
Ciência ID: 311B-86C6-1C9B

Isabel Santos, MSc
Clinical Biologist
Ciência ID: 0C13-B632-9D1D

Joana Guerra, MSc (IPOP)
Clinical Biologist
Ciência ID: EC17-9634-91E6

Joana Vieira, MSc
Clinical Biologist
Ciência ID: 751D-0AB6-2951

João Silva, MD
Genetician
Ciência ID: A217-7877-3BB1

Lurdes Torres, MSc
Clinical Biologist
Ciência ID: A113-39B0-F44B

Patrícia Arinto, MSc
Clinical Biologist
Ciência ID: 9F18-FB90-3ED9

Patrícia Rocha, MSc
Clinical Biologist
Ciência ID: 2715-3C44-24D7

Susana Bizarro, MSc
Clinical Biologist
Ciência ID: E011-B9A0-8B3F

Susana Lisboa, MSc
Clinical Biologist
Ciência ID: 2017-BE12-C7F5

AIMS

The main lines of research for the period 2024-2026 are the following:

1. To further characterize the contribution to carcinogenesis of the PRUNE2, BUB1B and IPO4 genes, which we have recently uncovered as candidate prostate cancer predisposition genes contributing to explain the missing heritability of this disease.
2. To understand the polygenic basis of hereditary predisposition to prostate cancer using a multi-omics integrative approach combining genomic and transcriptomic strategies.
3. To use cell-based strategies to screen genetic variants and compounds targeting cilia-related genes for prostate cancer development and therapy.
4. To evaluate the potential utility of anti-EGFR therapies in ETS-positive subtypes of prostate cancer.

PROJECTS WITH EXTERNAL FUNDING

PRUNE2 – “PRUNE2 gene as a novel dual-role biomarker for prostate cancer inherited predisposition and therapy response”; FCT (2023.01928.RESTART); Budget: 49,800€ (2023-2025) (PI: Andreia Brandão)

Building on previous findings, this project aims to combine genomic, transcriptomic, and computational approaches to consolidate PRUNE2 as a novel cancer predisposing gene for prostate cancer, and to evaluate its potential as a predictive biomarker.

Publications

Cardoso M, Maia S, Brandão A, Sahasrabudhe R, Lott P, Belter N, Carvajal-Carmona LG, Paulo P, Teixeira MR. Exome sequencing of affected duos and trios uncovers PRUNE2 as a novel prostate cancer predisposition gene. Br J Cancer. 2023; 128(6):1077-1085. doi: 10.1038/s41416-022-02125-6. PMID: 36564567.

PROJECTS WITH INTERNAL FUNDING

ctDNA-BRCA – “Identification of somatic and germline mutations in circulating tumor DNA in ovarian cancer patients and in germline BRCA1/BRCA2 mutation carriers undergoing cancer screening” (PI 71-CI-IPOP-35-2016), Budget: 90K€ (2016-2024) (PI: Manuel Teixeira)

This project aims to explore the use of ctDNA as an alternative for non-invasive predictive genetic testing for targeted therapy in ovarian cancer patients with germline or somatic BRCA1/2 mutations, as well as in the setting of cancer screening of high-risk germline BRCA1/2 mutation carriers.

Publications

Barbosa A, Pinto P, Peixoto A, Guerra J, Pinheiro M, Santos C, Pinto C, Escudeiro C, Bartosch C, Santos R, Brandão A, Silva J, Teixeira MR. Next generation sequencing of tumor and matched plasma samples: identification of somatic variants in ctDNA from ovarian cancer patients. Front Oncol. 2021; 11:754094. doi: 10.3389/fonc.2021.754094. PMID: 34660321.

Barbosa A, Peixoto A, Pinto P, Pinheiro M, Teixeira MR. Potential clinical applications of circulating cell-free DNA in ovarian cancer patients. Expert Rev Mol Med. 2018; 20:e6. doi: 10.1017/erm.2018.5. PMID: 30558693.

ctDNA-Cancer – “Validation of liquid biopsies for predictive biomarker testing, therapy response monitoring, and resistance mechanism identification in cancer patients” (PI 82-CI-IPOP-54-2017), Budget: 35K€ (2017-2024) (PI: Manuel Teixeira)

This project aims to evaluate the detection of genetic alterations in ctDNA as a tool for predictive biomarker testing, therapy response monitoring, and resistance mechanism identification in cancer patients candidates to or under treatment with biological cancer therapies.

Publications

Pinheiro M, Peixoto A, Rocha P, Veiga I, Pinto C, Santos C, Pinto P, Guerra J, Escudeiro C, Barbosa A, Silva J, Teixeira MR. KRAS and NRAS mutational analysis in plasma ctDNA from patients with metastatic colorectal cancer by real-time PCR and digital PCR. Int J Colorectal Dis. 2022; 37(4):895-905. doi: 10.1007/s00384-022-04126-6. PMID: 35303157.

CaGaGen – “Identification of germline mutations by gene-panel next generation sequencing in familial tubular and mixed tubular-diffuse gastric cancer” (PI 84-CI-IPOP-56-2017), Budget: 90K€ (2017-2024) (PI: Manuel Teixeira)

This project aims to identify additional genes involved in inherited predisposition to diffuse, tubular and mixed gastric cancer, which may allow genotype-oriented clinical surveillance and/or prophylaxis.

Publications:

Guerra J, Pinto C, Pinto P, Pinheiro M, Santos C, Peixoto A, Escudeiro C, Barbosa A, Porto M, Francisco I, Lopes P, Isidoro AR, Cunha AL, Albuquerque C, Claro I, Oliveira C, Silva J, Teixeira MR. Frequency of CDH1, CTNNA1 and CTNND1 germline variants in families with diffuse and mixed gastric cancer. Cancers (Basel). 2023; 15(17):4313. doi: 10.3390/cancers15174313. PMID: 37686589.

Fewings E, Larionov A, Redman J, Goldgraben MA, Scarth J, Richardson S, Brewer C, Davidson R, Ellis I, Evans DG, Halliday D, Izatt L, Marks P, McConnell V, Verbist L, Mayes R, Clark GR, Hadfield J, Chin SF, Teixeira MR, Giger OT, Hardwick R, di Pietro M, O’Donovan M, Pharoah P, Caldas C, Fitzgerald RC, Tischkowitz M. Germline pathogenic variants in PALB2 and other cancer-predisposing genes in families with hereditary diffuse gastric cancer without CDH1 mutation: a whole-exome sequencing study. Lancet Gastroenterol Hepatol. 2018; 3(7):489-498. doi: 10.1016/S2468-1253(18)30079-7. PMID: 29706558.

Sahasrabudhe R, Lott P, Bohorquez M, Toal T, Estrada AP, Suarez JJ, Brea-Fernández A, Cameselle-Teijeiro J, Pinto C, Ramos I, Mantilla A, Prieto R, Corvalan A, Norero E, Alvarez C, Tapia T, Carvallo P, Gonzalez LM, Cock-Rada A, Solano A, Neffa F, Della Valle A, Yau C, Soares G, Borowsky A, Hu N, He LJ, Han XY; Latin American Gastric Cancer Genetics Collaborative Group; Taylor PR, Goldstein AM, Torres J, Echeverry M, Ruiz-Ponte C, Teixeira MR, Carvajal-Carmona LG. Germline mutations in PALB2, BRCA1, and RAD51C, which regulate DNA recombination repair, in patients with gastric cancer. Gastroenterology. 2017; 152(5):983-986.e6. doi: 10.1053/j.gastro.2016.12.010. PMID: 28024868.

LUNG-ctDNA – “Characterization of targeted therapy resistance mechanisms in EGFR/ALK/ROS1/BRAF-positive NSCLC by gene panel NGS in circulating cell-free DNA” (PI 138-CI-IPOP-126-2019), Budget: 15K€ (2021-2024) (PI: Manuel Teixeira)

This project aims to evaluate the overall sensitivity of the NGS of ctDNA to detect the primary molecular change in NSCLC patients progressing after first-line targeted treatment with an approved targeted therapy for those molecular subtypes of NSCLC, to describe the pattern of resistance mechanisms in patients with EGFR, BRAF, ALK, or ROS1-positive NSCLC who progressed after first-line treatment, to evaluate the rate of potential access to other approved or off-label targeted therapies, and to evaluate the potential impact of this strategy to reduce the rate of rebiopsies in these patients.

VATER – “Landscape of somatic and germline genetic alterations in ampullary carcinomas” (PI 140-CI-IPOP-128-2020), Budget: 15K€ (2019-2024) (PI: Manuel Teixeira)

This project aims to perform screening of BRCA1/BRCA2 mutations in a large series of ampullary carcinomas to confirm the association of mutations in these genes with this rare neoplasia that we previously identified, to evaluate the presence of deleterious germline variants in other genes involved in DNA repair, namely, genes of the Fanconi anemia pathway and genes involved in HR, in patients with ampullary carcinomas, and to characterize the pattern of somatic variants in DNA repair genes in ampullary carcinomas.

MetPC – “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” (PI 141-CI-IPOP-129-2020), Budget: 75K€ (2021-2024) (PI: Manuel Teixeira)

This project aims to evaluate the feasibility and sensitivity of detecting both germline and somatic mutations in homologous recombination genes in cell-free circulation DNA (cfDNA) in patients with metastatic prostate cancer who do not have an analyzable formalin-fixed, paraffin-embedded tumor sample.

PATHSEARCH – “Understanding the polygenic basis of hereditary predisposition to prostate cancer: a multi-omics integrative approach combining genomics and transcriptomics” (PI 161-CI-IPOP-154-2021), Budget: 10K€ (2022-2028) (PI: Andreia Brandão)

This project aims to understand the polygenic basis of hereditary predisposition to prostate cancer using a multi-omics integrative approach combining genomic and transcriptomic strategies.

TREATCILIA – “Theragnostic exploitation of ciliogenesis defects in prostate cancer – building bridges” (PI 162-CI-IPOP-155-2021), Budget: 45K€ (2022-2025) (PI: Paula Paulo)

This project aims to use cell-based strategies to screen genetic variants and compounds targeting cilia-related genes for prostate cancer development and therapy.

POLYRISK – “Impact of multigene next generation sequencing and polygenic risk score for breast cancer predisposition” (PI 163-CI-IPOP-156-2021), Budget: 10K€ (2022-2024) (PI: Manuel Teixeira)

This project aims to evaluate the prevalence of pathogenic variants in BC susceptibility genes in BC patients who do not comply with the NICE criteria but who fulfill the MCGplus criteria for genetic testing.

ETS-EGFR-CRC – “Identification of markers of resistance to anti-EGFR therapy in colorectal carcinoma” (PI 205-CI-IPOP-08-2023), Budget: 5K€ (2023-2024) (PI: Paula Paulo)

This project aims to understand if expression of PEA3 transcription factors and/or GRPR are associated with resistance to anti-EGFR therapy in “wild-type” mCRCs, ultimately unveiling a molecular signature that may guide alternative therapeutic approaches.

HLEU – “Inherited predisposition to hematological malignancies” (PI 206-CI-IPOP-29-2023), Budget: 5K€ (2023-2024) (PI: Manuel Teixeira)

This project aims to detect germline variants that may be responsible for hereditary predisposition to hematological malignancies, with or without association with other neoplasias, in patients with personal and/or family history of the disease.

ETS-EGFR-PC – “In vitro exploitation of the therapeutic potential of EGFR pathway inhibitors in prostate cancer cells harboring ETS rearrangements” (PI 207-CI-IPOP-30-2023), Budget: 30K€ (2023-2024) (PI: Paula Paulo)

This project aims to evaluate the therapeutic potential of EGFR and STAT3 inhibitors in PCa cell lines overexpressing ETV1 or ETV4 in vitro, alone or in combination with a GRPR inhibitor.

ctDNA-Lynch – “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” (PI 72-CI-IPOP-36-2016), Budget: 20K€ (2016-2024) (PI: Manuel Teixeira)

This project aims to evaluate the detection of genetic alterations in ctDNA as a tool for early cancer diagnosis and follow up in high-risk Lynch syndrome patients and carriers.

SELECTED PUBLICATIONS

• Cardoso M, Maia S, Brandão A, Sahasrabudhe R, Lott P, Belter N, Carvajal-Carmona LG, Paulo P, Teixeira MR. Exome sequencing of affected duos and trios uncovers PRUNE2 as a novel prostate cancer predisposition gene. Br J Cancer. 2023; 128(6):1077-1085. doi: 10.1038/s41416-022-02125-6. PMID: 36564567.
• Paulo P, Cardoso M, Brandão A, Pinto P, Falconi A, Pinheiro M, Cerveira N, Silva R, Santos C, Pinto C, Peixoto A, Maia S, Teixeira MR. Genetic landscape of homologous recombination repair genes in early-onset/familial prostate cancer patients. Genes Chromosomes Cancer. 2023; 62(12):710-720. doi: 10.1002/gcc.23190. PMID: 37436117.
• Bancroft EK, Page EC, Brook MN, Thomas S, Taylor N, Pope J, McHugh J, Jones AB, Karlsson Q, Merson S, Ong KR, Hoffman J, Huber C, Maehle L, Grindedal EM, Stormorken A, Evans DG, Rothwell J, Lalloo F, Brady AF, Bartlett M, Snape K, Hanson H, James P, McKinley J, Mascarenhas L, Syngal S, Ukaegbu C, Side L, Thomas T, Barwell J, Teixeira MR, Izatt L, Suri M, Macrae FA, Poplawski N, Chen-Shtoyerman R, Ahmed M, Musgrave H, Nicolai N, Greenhalgh L, Brewer C, Pachter N, Spigelman AD, Azzabi A, Helfand BT, Halliday D, Buys S, Ramon Y Cajal T, Donaldson A, Cooney KA, Harris M, McGrath J, Davidson R, Taylor A, Cooke P, Myhill K, Hogben M, Aaronson NK, Ardern-Jones A, Bangma CH, Castro E, Dearnaley D, Dias A, Dudderidge T, Eccles DM, Green K, Eyfjord J, Falconer A, Foster CS, Gronberg H, Hamdy FC, Johannsson O, Khoo V, Lilja H, Lindeman GJ, Lubinski J, Axcrona K, Mikropoulos C, Mitra AV, Moynihan C, Ni Raghallaigh H, Rennert G, Collier R; IMPACT Study Collaborators; Offman J, Kote-Jarai Z, Eeles RA. A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initial results from an international prospective study. Lancet Oncol. 2021; 22(11):1618-1631. doi: 10.1016/S1470-2045(21)00522-2. PMID: 34678156.
• Brandão A, Paulo P, Maia S, Pinheiro M, Peixoto A, Cardoso M, Silva MP, Santos C, Eeles RA, Kote-Jarai Z, Muir K, Ukgpcs Collaborators, Schleutker J, Wang Y, Pashayan N, Batra J, Apcb BioResource, Grönberg H, Neal DE, Nordestgaard BG, Tangen CM, Southey MC, Wolk A, Albanes D, Haiman CA, Travis RC, Stanford JL, Mucci LA, West CML, Nielsen SF, Kibel AS, Cussenot O, Berndt SI, Koutros S, Sørensen KD, Cybulski C, Grindedal EM, Park JY, Ingles SA, Maier C, Hamilton RJ, Rosenstein BS, Vega A, The Impact Study Steering Committee And Collaborators, Kogevinas M, Wiklund F, Penney KL, Brenner H, John EM, Kaneva R, Logothetis CJ, Neuhausen SL, Ruyck K, Razack A, Newcomb LF, Canary Pass Investigators, Lessel D, Usmani N, Claessens F, Gago-Dominguez M, Townsend PA, Roobol MJ, The Profile Study Steering Committee, The Practical Consortium, Teixeira MR. The CHEK2 variant c.349A>G is associated with prostate cancer risk and carriers share a common ancestor. Cancers (Basel). 2020; 12(11):3254. doi: 10.3390/cancers12113254. PMID: 33158149.
• Paulo P, Maia S, Pinto C, Pinto P, Monteiro A, Peixoto A, Teixeira MR. Targeted next generation sequencing identifies functionally deleterious germline mutations in novel genes in early-onset/familial prostate cancer. PLoS Genet. 2018; 14(4):e1007355. doi: 10.1371/journal.pgen.1007355. PMID: 29659569.

PATENTS

(2012) Methods and biomarkers for detection of bladder cancer; US 20130210011/ EP 2630261 A1/ WO 2012052844 A1 (in collaboration Oslo University Hospital).

NATIONAL COLLABORATIONS

José Bessa, PhD | i3S
Hélder Maiato, PhD | i3S
Carla Oliveira, PhD | i3S
Joana Paredes, PhD | i3S

INTERNATIONAL COLLABORATIONS

Luis G Carvajal-Carmona, PhD
UC Davis Genome Center | USA

Rosalind Eeles, MD, PhD (PRACTICAL consortium and IMPACT study)
Institute of Cancer Research | UK

Georgia Chenevix-Trench, PhD, FAA (CIMBA consortium)
QIMR Berghofer Medical Research Institute | Australia

Douglas Easton, PhD (BCAC consortium)
University of Cambridge | UK

Amanda Spurdle, PhD (ENIGMA consortium)
QIMR Berghofer Medical Research Institute | Australia

Nicoline Hoogerbrugge, MD, PhD (European Reference Network on Genetic Tumour Risk Syndromes, GENTURIS)
Radboud university medical center | The Netherlands