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Dr. Raquel Seruca


The following information is provided by Dr. Raquel Seruca and her team at the Institute of Molecular Pathology and Immunology at the University of Porto (IPATIMUP) (June 2018)


Germline mutations in the CDH1 tumor suppressor gene predispose to a higher risk of hereditary diffuse gastric cancer and lobular breast cancer. In carriers of pathogenic germline CDH1 mutations prophylactic gastrectomy is recommended. In the particular case of germline missense variants (variants of uncertain significance- VUS), genetic counsellors are not able to predict if these alterations impact the correct function of E-cadherin just by the result of a standard genetic test. Thus, VUSs remain a clinical challenge since it is difficult to envisage the consequence of this genetic landscape for tumour development.

Therefore, it is mandatory to assess the functional impact on VUS in E-cadherin function in order to categorize these sequence variations, predict their clinical significance and, more importantly, to give patients and their families an informed genetic counselling. To fill this gap of knowledge, our group developed a panel of assays and tools, and established a pipeline to evaluate the functional consequences of the germline DNA alterations, improving genetic counselling of patients and families. Through bioinformatic analyses, image analysis, protein quantification, and a series of tests performed in transgenic cells in culture, it is obtained relevant information regarding possible pathogenic effects of most CDH1 VUS.

Bioinformatic analyses are performed to evaluate the putative impact of the germline VUS on RNA and also on E-cadherin protein structure and function. Predictions are based on the conservation of a particular DNA sequence among species, the particular site where it occurs within the gene, the type of substitutions in terms of aminoacids and on protein structural information. Despite all the data obtain on computational analysis being accessible to most labs around the world, clinicians and researchers should be aware of their limitations to evaluate VUS. In fact, there is no correlation between in silico analysis and the clinical impact of CDH1 VUS.

A series of tests performed in transgenic cells in culture, commonly denominated as in vitro assays, were thus implemented to investigate the effects of DNA variants (VUS) in the quantity of protein produced, its localization within the cell, and how this change affects the correct function of E-cadherin. E-cadherin is a very important protein that guaranties an organized tissue structure and a proper interaction between their cells, what is called a proficient cell-cell adhesion. When cells are unable to establish an efficient cell-cell adhesion due to mutations in the CDH1 gene, cells acquire the ability to invade the organ and the adjacent tissues, and in this way to cause invasive cancer since the very beginning of the disease.

To date, a large number of CDH1 germline VUS were found in different clinical settings and reported for functional evaluation at Seruca’s lab (IPATIMUP/i3S, Porto). The vast majority of them demonstrated to affect E-cadherin function. This information is sent to the genetic counsellors and to international colleagues that work in close collaboration with our group to improve the management and surveillance of HDGC patients and families. This work is performed without additional costs for the genetic labs that collaborate with us and for the patients. All services are free of charge, independently of the country or the institution that request the information.

If you have received a genetic test result of VUS alteration in the CDH1 gene, please have your genetic counselor contact us for information on how to obtain services for functional evaluation of your gene mutation at Seruca’s lab (IPATIMUP/i3S, Porto)

If you have received a genetic test result of a VUS alteration in the CDH1 gene, please consider joining the PROMPT: Prospective Registry Of MultiPlex Testing registry to advance research and follow the status of your variant.

Predicting the Functional Impact of CDH1 Missense Mutations in Hereditary Diffuse Gastric Cancer (2017)
Soraia Melo, Joana Figueiredo, Maria Sofia Fernandes, Margarida Gonçalves,
Eurico Morais-de-Sá, João Miguel Sanches and Raquel Seruca
Familial gastric cancer: Genetic susceptibility, pathology, and implications for management (2015)
Carla Oliveira, Hugo Pinheiro, Joana Figueiredo, Raquel Seruca, Fátima Carneiro
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