Study of CDH1 germline mutation in hereditary diffuse gastric cancer and lobular breast cancer: a multicenter study in Iran

Hereditary Diffuse Gastric Cancer: Diagnosis and Management

Hereditary Diffuse Gastric Cancer: Surveillance Endoscopy is Not Enough to Save Lives

Genetic Mutations Identified for Hereditary Diffuse Gastric Cancer

IntroductionGermline mutation in CDH1 (E-cadherin) tumor suppressor gene is associated with hereditary diffuse gastric cancer (HDGC) and lobular breast cancers (LBC). E-Cadherin protein is necessary for physiological signaling pathways, such as cell proliferation, maintenance of cell adhesion, cell polarity and epithelial-mesenchymal transition. Dysregulation leads to tumor proliferation, invasion, migration and metastases. We review current perspectives in CDH1 genetics with molecular mechanisms and also discuss management strategies for this aggressive form of gastric cancer.MethodsRelevant articles from PubMed/Medline and Embase (1994–2019) were searched and collected using the phrases “Hereditary diffuse gastric cancer, Familial gastric cancer, CDH1 mutation, E-Cadherin, Lobular breast cancer, Prophylactic total gastrectomy”.ResultsCurrent guidelines suggest maintaining a high degree of suspicion of hereditary etiology and recommend testing for CDH1 mutations in patients with familial clustering of HDGC and LBC, especially onset at an early age (before 40 years). In families lacking CDH1 mutations but with high suspicion for hereditary predisposition, testing of CTNNA1 and other closely related HDGC susceptibility genes could be considered. Prophylactic total gastrectomy is recommended for individuals with identified pathogenic germline variants. Endoscopic surveillance with biopsies is recommended for those choosing to delay prophylactic gastrectomy.ConclusionMutation or transcriptional silencing of the CDH1 gene is associated with familial diffuse gastric cancer. Further studies on the expression and the alteration in the proteins in the E-cadherin pathways may serve as biomarkers for early detection; stratify risk and selection of appropriate therapy in these families. Until then prophylactic total gastrectomy is recommended for individuals with CDH1 mutations and family history of diffuse gastric cancer. Endoscopic surveillance and biopsies by experienced gastroenterologists is recommended for those choosing not to have prophylactic gastrectomy and in individuals with CDH1 variants.

Accuracy of Hereditary Diffuse Gastric Cancer Testing Criteria and Outcomes in Patients With a Germline Mutation in CDH1

Background: The E-cadherin (CDH1) gene is involved in cell adhesion and maintenance of tissue architecture. Loss of expression of CDH1 has been found in both invasive lobular carcinoma (ILCA) of the breast as well as hereditary diffuse gastric cancer (HDGC). While mutations in CDH1 have been found in patients with hereditary diffuse gastric cancer, less is known about the role of CDH1 mutations in patients with breast cancer, thus mutation status was determined in a breast cancer cohort with and without family histories of gastric cancer. Methods: The Clinical Breast Care Project database was queried to identify all patients with ILCA with or without a family history of gastric or stomach cancer as well as those with non-lobular invasive cancer with a family history of gastric or stomach cancer. Genomic DNA was isolated from peripheral blood samples. DNA variants were detected for each exon using high-resolution melting technology and the underlying change identified by direct sequencing. Results: Of the 72 patients with ILCA, five had a first degree relative with stomach cancer; 14 patients with non-lobular invasive cancer (12 IDCA, one mixed lobular and ductal, and one tubular) had first degree relatives with stomach or gastric cancer. Three mutations previously associated with gastric cancer were identified: A617T and V832M were identified in a patient with ILCA with no history of gastric cancer and in a patient with IDCA with a family history of gastric cancer, respectively, while one patient with ILCA and no family history harbored the splice site mutation 1137G-T. Three novel variants were also identified: G879S, in a patient with ILCA and no family history, P825Q in a patient with mixed lobular and ductal features with a family history of stomach cancer and L230F in a patient with IDCA and a family history of stomach cancer. Conclusions: The frequency of CDH1 mutations in this patient population was low (∼7%) and were split between patients with ILCA and no family history of gastric cancer and those with non-lobular cancers and at least one family member with gastric or stomach cancer. Identification of known mutations in patients with non-lobular carcinomas suggests that while these specific CDH1 mutations are associated with increased risk of hereditary diffuse gastric cancer, they do not confer increased risk for lobular cancer. In those patients with ILCA, the low frequency of germline mutations in CDH1 suggests alternate methods, such as epigenetic modification or miRNA silencing, may be driving the suppression of expression of E-cadherin and the development of ILCA. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2202. doi:10.1158/1538-7445.AM2011-2202

BackgroundHereditary lobular breast cancer (HLBC) is a distinct subset of hereditary breast cancer primarily associated with germline pathogenic variants in the CDH1 gene, which encodes E-cadherin, a crucial protein in cell adhesion. Loss of E-cadherin disrupts tissue architecture, contributing to the invasive growth pattern characteristic of lobular carcinoma. CDH1 mutations are also implicated in hereditary diffuse gastric cancer, predisposing some patients to both cancers. However, variable cancer risk is observed, as many HLBC patients with a family history of gastric cancer do not develop gastric malignancies, reflecting the complex interplay of E-cadherin's role in cell cohesion and tumorigenesis.Main bodyHLBC accounts for 4–5% of lobular breast cancer cases, even in the absence of a personal or family history of gastric cancer. These tumors typically present as hormone receptor-positive (estrogen receptor-positive and progesterone receptor-positive) and are often diagnosed at advanced stages due to their diffuse growth pattern and subtle imaging characteristics. Recent evidence underscores the importance of genetic screening for CDH1 mutations in women with early-onset bilateral lobular breast cancer or a strong family history of breast cancer. Despite the strong correlation between CDH1 mutations and HLBC, the absence of diffuse gastric cancer in many patients presents diagnostic challenges. Updated guidelines emphasize targeted surveillance and risk-reduction strategies, including prophylactic mastectomy for high-risk individuals, aiming to improve clinical outcomes.ConclusionThis mini-review synthesizes recent advancements in understanding the genetics, diagnostic complexities, and clinical management of HLBC. The findings highlight the critical need for early identification and personalized approaches to optimize surveillance and therapeutic strategies for patients with this unique hereditary cancer.

Family History As a Positive Prognostic Factor in Gastric Cancer

Detection of multiple intramucosal signet-ring cell carcinomas by white-light endoscopy and magnifying endoscopy with narrow-band imaging in a hereditary diffuse gastric cancer patient with a CDH1 germline mutation.

Gaining Ground in the Genetics of Gastric Cancer

Persistent Nausea and Vomiting in Pregnancy

Hereditary diffuse gastric cancer (HDGC) is an autosomal-dominantly inherited cancer syndrome associated with a high risk for diffuse gastric and lobular breast cancer, caused by heterozygous CDH1 germline mutations. Of note, also cleft lip/palate (CLP) has been described in few HDGC families. Here we report on an extensive pedigree presenting with HDGC, CLP and a CDH1 splice site mutation (c.687 + 1G > A) and review the literature for families with CDH1 mutations, HDGC and CLP. Transcript analysis showed that the c.687 + 1G > A mutation leads to loss of the last 42bp of exon 5 and is consequently predicted to cause loss of 14 amino acids in the first extracellular cadherin repeat (EC) domain. Five mutation carriers developed diffuse gastric cancer and four individuals presented with CLP. Wild type CDH1 expression levels did not differ between CDH1 mutation carriers with CLP compared to those without CLP. Beside this extensive pedigree, we outline another previously unreported HDGC/CLP family with a CDH1 (c.1711 + 1G > C) germline mutation in this study. Review of the literature revealed a significant enrichment of CDH1 mutations within the EC domains in CLP/HDGC families (Fisher's exact test, p = 0.007) in comparison to CDH1 mutations associated with HDGC only. Report of further CLP/HDGC associated mutations is necessary to confirm this observation. This study highlights that CLP represents an important phenotypic feature of CDH1 germline mutation carriers and emphasizes the inclusion of CLP in the HDGC testing criteria. The underlying causes for the appearance of variable phenotypes in CDH1 mutation carriers could include genetic variation, epigenetic changes and environmental factors and should be investigated in future studies.

Confirmation of risk of cancer in blepharocheilodontic syndrome

BackgroundGermline mutations in CDH1 are associated with hereditary diffuse gastric cancer; lobular breast cancer also occurs excessively in families with such condition.MethodTo determine if CDH1 is a susceptibility gene for...

511PD - Germline Mutations in CDH1 and the Hereditary Diffuse Gastric and Lobular Breast Cancer Syndrome