Abstract
Germline mutations of the E-cadherin gene (CDH1) are involved in the tumorigenesis of hereditary diffuse gastric cancer (HDGC). Recent studies have highlighted the lifesaving potential of total prophylactic gastrectomy for CDH1 germline mutation carriers. In this regard, CDH1 germline mutations of the missense type represent a clinical burden in genetic counseling, as their pathogenic relevance is not straightforward. In this work, we have outlined a possible multivariate approach to infer the significance of such variants. We reviewed all HDGC-associated E-cadherin germline missense mutations reported to date. The information collected included: co-segregation of the mutation within pedigrees, frequency in healthy population control, recurrence in independent families, and functional in vitro and in silico data. We used the neighbor-joining method to group mutations according to the collected information and assessed the robustness of mutation clusters with a bootstrap test. CDH1 germline missense variants were classified according to the parameters defined in the multivariate analysis. This analysis allowed the distribution of the variants into two distinct groups: neutral variants vs mutations. The model described in this study provides an important tool that can ultimately improve the genetic counseling offered to the carriers of the germline CDH1 missense variants.
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Acknowledgements
We thank Dr. Bostjan Humar, Cancer Genetics Biochemistry Department, University of Otago, New Zealand, who provided us the HDGC-associated germline missense mutations T118R and G239R and also Dr. Fiona Macdonald, head of DNA Section, West Midlands Regional Genetics Laboratory, UK, for data on the L214P mutation. This work was supported by Fundação para a Ciência e a Tecnologia, Portugal, grant numbers REEQ/218/SAU/2005 and POCI/SAU-OBS/57670/2004, and Agencia de Inovação, grant number INV-ONC-DPN. Susana Seixas is a recipient of a post-doc fellowship sponsored by Fundação para a Ciência e a Tecnologia, Portugal (FCTBPD/12532/2003).
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Suriano, G., Seixas, S., Rocha, J. et al. A model to infer the pathogenic significance of CDH1 germline missense variants. J Mol Med 84, 1023–1031 (2006). https://doi.org/10.1007/s00109-006-0091-z
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DOI: https://doi.org/10.1007/s00109-006-0091-z