Clinical and functional characterization of the CDH1 germline variant c.1679C&gt;G in three unrelated families with hereditary diffuse gastric cancer

Pena-Couso, Laura; Perea, José; Melo, Soraia; Mercadillo, Fátima; Figueiredo, Joana; Sanches, J. Miguel; Sánchez-Ruiz, Antonio Carlos; Robles, Luis; Seruca, Raquel; Urioste, Miguel

doi:10.1038/s41431-018-0173-8

Cited by 11 publications

(8 citation statements)

References 15 publications

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“…For the family study articles, we collected data on country (or ethnicity), mutation type and classification, age of proband, total number of screened subjects harbouring CDH1 mutations, number of carriers affected by gastric cancer, and number of carriers affected by other cancer types ( Table S2 ) [ 18 , 37 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 ]. Mean age of CDH1 mutation carriers affected by gastric cancer and mean age of carriers affected by other cancer types was also determined.…”

Section: Methodsmentioning

confidence: 99%

Geographical Distribution of E-cadherin Germline Mutations in the Context of Diffuse Gastric Cancer: A Systematic Review

Corso

Bellerba

et al. 2021

Cancers

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Hereditary diffuse gastric cancer (HDGC) is a complex and multifactorial inherited cancer predisposition syndrome caused by CDH1 germline mutations. Nevertheless, current CDH1 genetic screening recommendations disregard an unbalanced worldwide distribution of CDH1 variants, impacting testing efficacy and patient management. In this systematic review, we collected and analyzed all studies describing CDH1 variants in gastric cancer patients originating from both high- and low-prevalence countries. Selected studies were categorized as family study, series study, and unknown study, according to the implementation of HDGC clinical criteria for genetic testing. Our results indicate that CDH1 mutations are more frequently identified in gastric cancer low-incidence countries, and in the family study group that encompasses cases fulfilling criteria. Considering the type of CDH1 alterations, we verified that the relative frequency of mutation types varies within study groups and geographical areas. In the series study, the missense variant frequency is higher in high-incidence areas of gastric cancer, when compared with non-missense mutations. However, application of variant scoring for putative relevance led to a strong reduction of CDH1 variants conferring increased risk of gastric cancer. Herein, we demonstrate that criteria for CDH1 genetic screening are critical for identification of individuals carrying mutations with clinical significance. Further, we propose that future guidelines for testing should consider GC incidence across geographical regions for improved surveillance programs and early diagnosis of disease.

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Section: Methodsmentioning

confidence: 99%

Geographical Distribution of E-cadherin Germline Mutations in the Context of Diffuse Gastric Cancer: A Systematic Review

Corso

Bellerba

et al. 2021

Cancers

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“…Immunostaining and its detailed quantitative analysis is then used to address whether the variant induces abnormal patterns of E-cadherin localization [136]. Occasionally, a band mobility shift can also be observed, suggesting aberrant glycosylation of the protein [138,139]. Contrary to wild-type E-cadherin, which is normally present at the plasma membrane, deleterious variants can be diffusely distributed throughout the cell or abnormally accumulated in cytoplasmic regions/organelles [135,136,140].…”

Section: Cdh1 Missense Variants: Challenging Routine Laboratory Testsmentioning

confidence: 99%

Hereditary Gastric and Breast Cancer Syndromes Related to CDH1 Germline Mutation: A Multidisciplinary Clinical Review

Corso

Montagna

Figueiredo

et al. 2020

Cancers

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E-cadherin (CDH1 gene) germline mutations are associated with the development of diffuse gastric cancer in the context of the so-called hereditary diffuse gastric syndrome, and with an inherited predisposition of lobular breast carcinoma. In 2019, the international gastric cancer linkage consortium revised the clinical criteria and established guidelines for the genetic screening of CDH1 germline syndromes. Nevertheless, the introduction of multigene panel testing in clinical practice has led to an increased identification of E-cadherin mutations in individuals without a positive family history of gastric or breast cancers. This observation motivated us to review and present a novel multidisciplinary clinical approach (nutritional, surgical, and image screening) for single subjects who present germline CDH1 mutations but do not fulfil the classic clinical criteria, namely those identified as—(1) incidental finding and (2) individuals with lobular breast cancer without family history of gastric cancer (GC).

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“…Here we present an HDGC family with a missense CDH1 substitution variant, c.1679C>G (p.T560R). The p.T560R variant had been reported three times in patients with HDGC[ 11 - 13 ]. Yelskaya et al [ 12 ] reported that the p.T560R mutation created a novel 5¢ splice donor site that led to truncation of E-cadherin.…”

Section: Discussionmentioning

confidence: 99%

“…Yelskaya et al [ 12 ] reported that the p.T560R mutation created a novel 5¢ splice donor site that led to truncation of E-cadherin. Furthermore, Pena-Couso et al [ 13 ] performed functional analyses, which revealed that the p.T560R mutation causes an abnormal pattern of E-cadherin expression in the cytoplasm, disrupts cell-cell adhesion and promotes cellular invasion. Consistent with these reports, loss of E-cadherin expression at SRCC foci was observed in Case 3.…”

Section: Discussionmentioning

confidence: 99%

Case series of three patients with hereditary diffuse gastric cancer in a single family: Three case reports and review of literature

Hirakawa

Takada

Sato

et al. 2020

WJG

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BACKGROUND Hereditary diffuse gastric cancer (HDGC) is a familial cancer syndrome often associated with germline mutations in the CDH1 gene. However, the frequency of CDH1 mutations is low in patients with HDGC in East Asian countries. Herein, we report three cases of HDGC harboring a missense CDH1 variant, c.1679C>G, from a single Japanese family. CASE SUMMARY A 26-year-old female (Case 1) and a 51-year-old male (father of Case 1), who had a strong family history of gastric cancer, were diagnosed with advanced diffuse gastric cancer. After genetic counselling, a 25-year-old younger brother of Case 1 underwent surveillance esophagogastroduodenoscopy that detected small signet ring cell carcinoma foci as multiple pale lesions in the gastric mucosa. Genetic analysis revealed a CDH1 c.1679C>G variant in all three patients. CONCLUSION It is important for individuals suspected of having HDGC to be actively offered genetics evaluation. This report will contribute to an increased awareness of HDGC.

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Clinical and functional characterization of the CDH1 germline variant c.1679C>G in three unrelated families with hereditary diffuse gastric cancer

Cited by 11 publications

References 15 publications

Geographical Distribution of E-cadherin Germline Mutations in the Context of Diffuse Gastric Cancer: A Systematic Review

Geographical Distribution of E-cadherin Germline Mutations in the Context of Diffuse Gastric Cancer: A Systematic Review

Hereditary Gastric and Breast Cancer Syndromes Related to CDH1 Germline Mutation: A Multidisciplinary Clinical Review

Case series of three patients with hereditary diffuse gastric cancer in a single family: Three case reports and review of literature

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