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Revisiting the Biological and Clinical Impact of CDH1 Missense Variants

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Hereditary Gastric and Breast Cancer Syndrome

Abstract

E-cadherin, encoded by CDH1, plays an undisputable role in mechanical and biochemical signals that are crucial for cell integrity and tissue organization. Hence, E-cadherin deregulation results in severe tissue imbalances as those seen in cancer and congenital disorders. In particular, hereditary diffuse gastric cancer, lobular breast cancer, cleft lip/palate, and the blepharocheilodontic syndrome have been recognized as CDH1-associated entities. Among a plethora of CDH1 genetic alterations identified in disease contexts, missense variants represent a huge burden for genetic counselling and patient management. Indeed, establishment of their biological and clinical impact is not always straightforward, contributing to misestimation and inaccurate classification. Herein, we provide an overview of the state of the art concerning CDH1 missense variants, their geographical distribution and their relevance in distinct clinical spectra. We highlight the unequivocal value of an integrative pipeline to assess functional significance of variants, encompassing familial and population data analysis, in silico modelling, in vitro assays and in vivo studies. Importantly, we discuss how this strategy may improve genetic counselling of patients and their families, whilst opening up avenues of research addressing the aetiology of E-cadherin-mediated disorders.

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Acknowledgements

We would like to pay a tribute to Raquel Seruca, our forever inspiring mentor. To infinity and beyond.

Funding

This work was financed by FEDER funds through the Operational Programme for Competitiveness Factors (COMPETE 2020), Programa Operacional de Competitividade e Internacionalização (POCI) and Programa Operacional Regional do Norte (Norte 2020); and by National Funds through the Portuguese Foundation for Science and Technology (FCT projects PTDC/MED-GEN/30356/2017, EXPL/MED-ONC/0386/2021, 2022.02665.PTDC, and doctoral grant SFRH/BD/143533/2019-JP). We acknowledge the American Association of Patients with Hereditary Gastric Cancer “No Stomach for Cancer” for funding Seruca’s research, and the project “P.CCC: Centro Compreensivo de Cancro do Porto” - NORTE-01-0145-FEDER-072678, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF).

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Authors and Affiliations

  1. i3S – Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal

    Joana Pereira, Soraia Melo, Patrícia Carneiro, Maria Sofia Fernandes, Joana Figueiredo & Raquel Seruca

  2. Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal

    Joana Pereira, Soraia Melo, Patrícia Carneiro, Maria Sofia Fernandes, Joana Figueiredo & Raquel Seruca

  3. Medical Faculty of the University of Porto, Porto, Portugal

    Joana Pereira, Joana Figueiredo & Raquel Seruca

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  1. Joana Pereira
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  2. Soraia Melo
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  4. Maria Sofia Fernandes
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Correspondence to Joana Figueiredo .

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  1. European Institute of Oncology, University of Milan, Milan, Italy

    Giovanni Corso

  2. European Institute of Oncology, University of Milan, Milan, Italy

    Paolo Veronesi

  3. University of Siena, Siena, Italy

    Franco Roviello

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Pereira, J., Melo, S., Carneiro, P., Fernandes, M.S., Figueiredo, J., Seruca, R. (2023). Revisiting the Biological and Clinical Impact of CDH1 Missense Variants. In: Corso, G., Veronesi, P., Roviello, F. (eds) Hereditary Gastric and Breast Cancer Syndrome. Springer, Cham. https://doi.org/10.1007/978-3-031-21317-5_6

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