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Clinical spectrum and pleiotropic nature of CDH1 germline mutations
  1. Joana Figueiredo1,2,
  2. Soraia Melo1,2,3,
  3. Patrícia Carneiro1,2,
  4. Ana Margarida Moreira1,3,2,
  5. Maria Sofia Fernandes1,2,4,
  6. Ana Sofia Ribeiro1,2,
  7. Parry Guilford5,
  8. Joana Paredes1,3,2,
  9. Raquel Seruca1,3,2
  1. 1 Epithelial Interactions in Cancer Department, Instituto de Investigação e Inovação em Saúde (i3S), Porto, Portugal
  2. 2 Epithelial Interactions in Cancer, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
  3. 3 Medical Faculty of the University of Porto, Porto, Portugal
  4. 4 Institute for Systems and Robotics (ISR/IST), LARSyS, Bioengineering Department, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
  5. 5 Cancer Genetics Laboratory, Centre for Translational Cancer Research (Te Aho Matatū), Department of Biochemistry, University of Otago, Dunedin, New Zealand
  1. Correspondence to Dr Joana Figueiredo, Instituto de Investigação e Inovação em Saúde (i3S), Porto 4200-135, Portugal; jfigueiredo{at}


CDH1 encodes E-cadherin, a key protein in adherens junctions. Given that E-cadherin is involved in major cellular processes such as embryogenesis and maintenance of tissue architecture, it is no surprise that deleterious effects arise from its loss of function. E-cadherin is recognised as a tumour suppressor gene, and it is well established that CDH1 genetic alterations cause diffuse gastric cancer and lobular breast cancer—the foremost manifestations of the hereditary diffuse gastric cancer syndrome. However, in the last decade, evidence has emerged demonstrating that CDH1 mutations can be associated with lobular breast cancer and/or several congenital abnormalities, without any personal or family history of diffuse gastric cancer. To date, no genotype–phenotype correlations have been observed. Remarkably, there are reports of mutations affecting the same nucleotide but inducing distinct clinical outcomes. In this review, we bring together a comprehensive analysis of CDH1-associated disorders and germline alterations found in each trait, providing important insights into the biological mechanisms underlying E-cadherin’s pleiotropic effects. Ultimately, this knowledge will impact genetic counselling and will be relevant to the assessment of risk of cancer development or congenital malformations in CDH1 mutation carriers.

  • e-cadherin disorders
  • cdh1 mutation
  • hereditary diffuse gastric cancer (hdgc)
  • lobular breast cancer
  • cleft lip/palate

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  • Contributors JF was responsible for study concept and design. JF, SM, PC, AMM, MSF and ASR have drafted the article. PG, JP and RS critically reviewed the manuscript for important intellectual content. All authors approved the final version of the manuscript.

  • Funding This work was financed by FEDER funds through the Operational Programme for Competitiveness Factors (COMPETE 2020), Programa Operacional de Competitividade e Internacionalização, Programa Operacional Regional do Norte (Norte 2020) and by National Funds through the Portuguese Foundation for Science and Technology, under the projects PTDC/MED-GEN/30356/2017, PTDC/BIM-ONC/0171/2012, PTDC/BIM-ONC/0281/2014, PTDC/BBB-IMG/0283/2014, NORTE-01-0145-FEDER-000029; postdoctoral grant SFRH/BPD/87705/2012-JF and doctoral grants SFRH/BD/108009/2015-SM and SFRH/BD/114687/2016-AMM. We acknowledge the American Association of Patients with Hereditary Gastric Cancer ’No Stomach for Cancer' for funding RS and FJ’s research.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Patient consent for publication Not required.

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