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A novel CDH1 germline missense mutation in a sporadic gastric cancer patient in north-east of Italy

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Abstract

It is well documented that germline mutations in the E-cadherin (CDH1) gene are linked to hereditary diffuse gastric cancer (HDGC). Despite the known molecular genetic causes, most gastric cancers are sporadic and poorly investigated for susceptibility genes. We report the finding of a novel germline missense mutation in exon 6, c. 820 G > A (p.G274S) in one sporadic gastric cancer patient. This new variant does not affect cryptic splicing of CDH1 as demonstrated by molecular assay. Immunohistochemical analysis shows a mixed pattern of E-cadherin staining (membranous and cytoplasmic) in the intestinal component, while in the diffuse counterpart, the membranous staining was prevalent and a reduced membranous expression of ß-catenin was observed. In vitro assays suggest that the mutant G274S does not affect the E-cadherin protein function, its expression pattern or subcellular localization. This new variant is present in EC2 extracellular domain of the protein (p.G120S in mature protein). The molecular modelling shows that this point mutation is not dramatic for local structure. However, p.S120 is located on the surface of the protein close to the functional calcium sites and in the region of interaction with EC1 domain of another E-cadherin molecule involved in the formation of the intercellular junction. Moreover, p.S120 residue could be involved in posttranslational modifications, such as phosphorylation or glycosylation, with possible effects on stability and integrity of adhesive properties of E-cadherin. In conclusion, the pathogenicity of this mutation is unlikely; probably we found a new germline CDH1 missense mutation with potential impact, however, of uncertain significance.

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Acknowledgments

The authors thank Dr. Stefania Maiero of the Gastroenterology Unit for medical support and Dr Paola Ceolin, Dr Antonella Selva and Dr Barbara Canal of Pathology Unit for their collaborative technical assistance. This work was supported by Projects: Multidimensional Characterization of Solid Tumors, Regionale FVG R3A2, and Associazione Italiana per la Ricerca sul Cancro (AIRC n.10266, AIRC n. 12214).

Conflict of interest

Authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Experimental and Clinical Pharmacology Unit, Department of Molecular Oncology and Translational Medicine, DOMERT, IRCCS, National Cancer Institute, Centro di Riferimento Oncologico, Via F. Gallini, 2, 33081, Aviano, PN, Italy

    Marica Garziera, Valli De Re, Laura Caggiari, Mariangela De Zorzi & Giuseppe Toffoli

  2. Department of Chemical and Pharmaceutical Sciences, Centre of Excellence in Biocrystallography (CEB), University of Trieste, Trieste, Italy

    Silvano Geremia

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

    Raquel Seruca, Joana Figueiredo, Soraia Melo & Joana Simões-Correia

  4. Faculty of Medicine, University of Porto, Porto, Portugal

    Raquel Seruca & Joana Figueiredo

  5. Centre of Ophthalmology and Vision Sciences–IBILI, University of Coimbra, Coimbra, Portugal

    Joana Simões-Correia

  6. Pathology Unit, National Cancer Institute, IRCCS, Aviano, Italy

    Vincenzo Canzonieri

  7. Gastroenterology Unit, National Cancer Institute, IRCCS, Aviano, Italy

    Renato Cannizzaro

Authors
  1. Marica Garziera
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  2. Valli De Re
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  3. Silvano Geremia
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  4. Raquel Seruca
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  5. Joana Figueiredo
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  6. Soraia Melo
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  7. Joana Simões-Correia
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  8. Laura Caggiari
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  9. Mariangela De Zorzi
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  10. Vincenzo Canzonieri
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  11. Renato Cannizzaro
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  12. Giuseppe Toffoli
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Corresponding author

Correspondence to Valli De Re.

Additional information

Marica Garziera and Valli De Re have contributed equally to this work.

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Garziera, M., De Re, V., Geremia, S. et al. A novel CDH1 germline missense mutation in a sporadic gastric cancer patient in north-east of Italy. Clin Exp Med 13, 149–157 (2013). https://doi.org/10.1007/s10238-012-0184-7

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  • DOI: https://doi.org/10.1007/s10238-012-0184-7

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