A RAND/UCLA appropriateness study of the management of familial gastric cancer.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 16-16
Author(s):  
Matthew Dixon ◽  
Rajini Seevaratnam ◽  
Debrah Wirtzfeld ◽  
Robin S. McLeod ◽  
Lucy K. Helyer ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gastric Cancer ◽  
Expert Panel ◽  
Diffuse Gastric Cancer ◽  
Lobular Breast Cancer ◽  
Mutation Status ◽  
Prophylactic Gastrectomy ◽  
Cdh1 Mutation ◽  
Risk Patients ◽  
History Of

16 Background: Hereditary diffuse gastric cancer (HDGC) makes up 0.1-0.3% of all gastric cancers. Management of patients with HDGC is inconsistent and there is disagreement regarding management. Methods: A multi-disciplinary expert panel of 16 physicians from 6 countries scored 47 scenarios using the RAND/UCLA Appropriateness Methodology. Appropriateness was scored from 1 (highly inappropriate) to 9 (highly appropriate). Median appropriateness scores (AS) from 1-3 were considered inappropriate, 4−6 uncertain, and 7−9, appropriate. Agreement was reached when 11 of 16 panelists scored the statement similarly. If a statement was agreed to be appropriate, it was given a necessity score (NS) in the same manner. AS and NS are reported if agreement was met. Results: Gastric cancer (GC) patients with a family history of diffuse gastric cancer (DGC), lobular breast cancer or multiple family members with GC should be referred for genetics assessment and multidisciplinary decision-making (AS 8.0). It is appropriate for patients with DGC to have CDH1 mutation testing in a family with: (1) two or more cases of GC, with at least one case of DGC diagnosed before the age of 50 (AS 8.0); (2) three or more cases of GC diagnosed at any age, one or more of which is DGC (AS 8.0); (3) a patient diagnosed with DGC and lobular breast cancer (AS 8.0); or (4) a patient diagnosed with DGC under the age of 35 (AS 7.0, NS 5.0). A prophylactic total gastrectomy should be offered to CDH1 mutation carriers 20 years or older (AS 7.0). Conclusions: The Gastric Cancer Processes of Care panelists have outlined high risk patients in whom CDH1 mutation status should be determined, and cases in which a prophylactic gastrectomy is appropriate.

Prevalence of CDH1 germline mutations in subjects with early onset or familial lobular breast cancer, a multicenter collaboration

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 11042-11042
Author(s):  
S. Masciari ◽  
K. A. Schrader ◽  
J. Senz ◽  
N. Tung ◽  
J. Balmana ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gastric Cancer ◽  
Family History ◽  
Early Onset ◽  
Direct Sequencing ◽  
Familial Cancer ◽  
Germline Mutations ◽  
Diffuse Gastric Cancer ◽  
Prophylactic Gastrectomy ◽  
History Of

11042 Background: Invasive lobular breast carcinoma (LBC) is part of the hereditary diffuse gastric cancer (HDGC) syndrome, associated with germline mutations in the E-cadherin (CDH1) gene. CDH1 mutations can be identified in 80% of families ascertained by DGC. The risk of DGC in CDH1 mutation carriers is 67% in males, and 83% in females; the estimated risk of LBC in women is 39–50% to age 80. Management of HDGC includes prophylactic gastrectomy. In this study, we estimated the prevalence of germline CDH1mutations among women with LBC who were either diagnosed at young age or had family history of breast cancer (BC). Methods: Germline DNA was collected from 383 women with LBC or mixed, lobular/ductal, BC from breast cancer programs, familial cancer clinics, and population-based cohorts. Germline BRCA1or BRCA2mutations carriers were excluded. Eligible women had (1) LBC before age 45 or (2) LBC at any age with at least two 1st or 2nd degree relatives with BC of any type. Denaturing high pressure liquid chromatography was undertaken, followed by direct sequencing of exons displaying changes. Results: At the time of submission 310 of 383 samples have been fully sequenced. One previously characterized missense mutation and four novel non-synonymous variants (1.6%) were found. Three of these women had LBC before 45 years and no family history of BC; two had BC family history. No gastric cancers were reported in these families. Functional assays to assess the pathogenicity of the variants are in process. Conclusions: These results confirm that CDH1 is responsible for a small proportion of familial and early onset LBC. Given the difficulty of identifying CDH1 mutations from BC history alone and the importance of managing the gastric cancer risk in CDH1carriers, these findings should underscore the need to obtain an accurate abdominal cancer family history from women with LBC. No significant financial relationships to disclose.

scholarly journals Clinical spectrum and pleiotropic nature of CDH1 germline mutations

2019 ◽  
Vol 56 (4) ◽  
pp. 199-208 ◽  
Author(s):  
Joana Figueiredo ◽  
Soraia Melo ◽  
Patrícia Carneiro ◽  
Ana Margarida Moreira ◽  
Maria Sofia Fernandes ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gastric Cancer ◽  
Genetic Alterations ◽  
Tumour Suppressor Gene ◽  
Diffuse Gastric Cancer ◽  
Loss Of Function ◽  
Lobular Breast Cancer ◽  
Cancer Syndrome ◽  
Risk Of Cancer ◽  
E Cadherin

CDH1 encodes E-cadherin, a key protein in adherens junctions. Given that E-cadherin is involved in major cellular processes such as embryogenesis and maintenance of tissue architecture, it is no surprise that deleterious effects arise from its loss of function. E-cadherin is recognised as a tumour suppressor gene, and it is well established that CDH1 genetic alterations cause diffuse gastric cancer and lobular breast cancer—the foremost manifestations of the hereditary diffuse gastric cancer syndrome. However, in the last decade, evidence has emerged demonstrating that CDH1 mutations can be associated with lobular breast cancer and/or several congenital abnormalities, without any personal or family history of diffuse gastric cancer. To date, no genotype–phenotype correlations have been observed. Remarkably, there are reports of mutations affecting the same nucleotide but inducing distinct clinical outcomes. In this review, we bring together a comprehensive analysis of CDH1-associated disorders and germline alterations found in each trait, providing important insights into the biological mechanisms underlying E-cadherin’s pleiotropic effects. Ultimately, this knowledge will impact genetic counselling and will be relevant to the assessment of risk of cancer development or congenital malformations in CDH1 mutation carriers.

Hereditary lobular breast cancer with an emphasis on E-cadherin genetic defect

2018 ◽  
Vol 55 (7) ◽  
pp. 431-441 ◽  
Author(s):  
Giovanni Corso ◽  
Joana Figueiredo ◽  
Carlo La Vecchia ◽  
Paolo Veronesi ◽  
Gabriella Pravettoni ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Family History ◽  
Age At Onset ◽  
Genetic Defect ◽  
Prophylactic Surgery ◽  
Current Evidence ◽  
Diffuse Gastric Cancer ◽  
Lobular Breast Cancer ◽  
Clinicopathological Findings ◽  
History Of

Recent studies have reported germline CDH1 mutations in cases of lobular breast cancer (LBC) not associated with the classical hereditary diffuse gastric cancer syndrome. A multidisciplinary workgroup discussed genetic susceptibility, pathophysiology and clinical management of hereditary LBC (HLBC). The team has established the clinical criteria for CDH1 screening and results’ interpretation, and created consensus guidelines regarding genetic counselling, breast surveillance and imaging techniques, clinicopathological findings, psychological and decisional support, as well as prophylactic surgery and plastic reconstruction. Based on a review of current evidence for the identification of HLBC cases/families, CDH1 genetic testing is recommended in patients fulfilling the following criteria: (A) bilateral LBC with or without family history of LBC, with age at onset <50 years, and (B) unilateral LBC with family history of LBC, with age at onset <45 years. In CDH1 asymptomatic mutant carriers, breast surveillance with clinical examination, yearly mammography, contrast-enhanced breast MRI and breast ultrasonography (US) with 6-month interval between the US and the MRI should be implemented as a first approach. In selected cases with personal history, family history of LBC and CDH1 mutations, prophylactic mastectomy could be discussed with an integrative group of clinical experts. Psychodecisional support also plays a pivotal role in the management of individuals with or without CDH1 germline alterations. Ultimately, the definition of a specific protocol for CDH1 genetic screening and ongoing coordinated management of patients with HLBC is crucial for the effective surveillance and early detection of LBC.

scholarly journals Change of natural history of hereditary diffuse gastric cancer after identification of a novel CDH1 mutation

2017 ◽  
Vol 28 ◽  
pp. v503
Author(s):  
N. Stjepanovic ◽  
S. Castro ◽  
N. Gadea ◽  
E. Carrasco ◽  
M. Codina ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Natural History ◽  
Hereditary Diffuse Gastric Cancer ◽  
Diffuse Gastric Cancer ◽  
Cdh1 Mutation ◽  
History Of

Hereditary diffuse gastric cancer: Natural history, pathology, screening limitations, and prophylactic total gastrectomy in CDH1 mutation carriers

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4500-4500 ◽  
Author(s):  
H. T. Lynch ◽  
C. Caldas ◽  
D. Wirtzfeld ◽  
C. Vaccaro ◽  
W. Rubinstein ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Genetic Counseling ◽  
Total Gastrectomy ◽  
Mutation Testing ◽  
Hereditary Diffuse Gastric Cancer ◽  
Diffuse Gastric Cancer ◽  
Mutation Carriers ◽  
Prophylactic Gastrectomy ◽  
Cdh1 Mutation ◽  
Prophylactic Total Gastrectomy

4500 Background: Hereditary diffuse gastric cancer (HDGC) is a potentially fatal disease that occurs due to mutations in the E- cadherin (CDH1) gene, as discovered in 1998. Its penetrance ranges between 70–80%. Its morbidity and mortality can be altered favorably through genetic counseling, germline mutation testing, and highly-targeted management that includes prophylactic total gastrectomy. Lobular breast cancer has been identified as an integral lesion in HDGC. Methods: This international collaborative group on HDGC is comprised of 56 mutation-positive families, which is the world’s largest resource of such families. Cancer diagnoses were verified with pathology slides/tissue block review when possible, or reports. Genetic counseling covering the pros and cons of mutation testing, screening and its limitations, and the option of prophylactic total gastrectomy was provided. Results: Findings on 56 HDGC mutation-positive families show carrier testing to have been performed on 267 individuals, of which 123 were CDH1 mutation positive. Prophylactic gastrectomies were performed on 14 families involving 50 individuals. Occult cancer was diagnosed in 31 (31/39=79.5%; results are pending on the remaining 11), based upon pathology and verbal reports. Five individuals underwent prophylactic gastrectomy prior to genetic counseling, 3 of whom later tested negative for mutations. In one of these remarkable HDGC families, 11 first cousins who tested positive for the CDH1 mutation underwent prophylactic total gastrectomy. On a post-surgery questionnaire, they each stated that the decision for the prophylactic procedure was the “right one” for them. In each case, a parent had died of HDGC sequelae, adding to the cousins’ acceptance of DNA testing and surgery. They considered their post-operative nutritional programs to have been acceptable. Conclusion: HDGC and its life-threatening sequelae were significantly ameliorated in CDH1 mutation carriers through total prophylactic gastrectomy in patients at enormous lifetime risk for HDGC. Decision for mutation testing and surgery may be more acceptable through intensive education in concert with a compassionate management team. No significant financial relationships to disclose.

Co-occurrence of germline BRCA1 and CDH1 pathogenic variants

2020 ◽  
pp. jmedgenet-2020-106972
Author(s):  
Marie-Charlotte Villy ◽  
Emmanuelle Mouret-Fourme ◽  
Lisa Golmard ◽  
Véronique Becette ◽  
Nasrine Callet ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gastric Cancer ◽  
Genetic Counselling ◽  
Familial Breast Cancer ◽  
Large Deletion ◽  
Diffuse Gastric Cancer ◽  
Complex Situation ◽  
Pathogenic Variants ◽  
History Of ◽  
Paternal Grandmother

Introduction: We report a very rare case of familial breast cancer and diffuse gastric cancer, with germline pathogenic variants in both BRCA1 and CDH1 genes. To the best of our knowledge, this is the first report of such an association.Family description: The proband is a woman diagnosed with breast cancer at the age of 52 years. She requested genetic counselling in 2012, at the age of 91 years, because of a history of breast cancer in her daughter, her sister, her niece and her paternal grandmother and was therefore concerned about her relatives. Her sister and maternal aunt also had gastric cancer. She was tested for several genes associated with hereditary breast cancer.Results: A large deletion of BRCA1 from exons 1 to 7 and two CDH1 pathogenic cis variants were identified.Conclusion: This complex situation is challenging for genetic counselling and management of at-risk individuals.

scholarly journals Hereditary Gastric Cancer: Review of Literature

2013 ◽  
Vol 13 (1) ◽  
pp. 71-74
Author(s):  
Jelena Pogodina ◽  
Genadijs Trofimovics ◽  
Edvins Miklasevics ◽  
Roberts Ribenieks
Keyword(s):  
Gastric Cancer ◽  
Future Research ◽  
Diffuse Gastric Cancer ◽  
High Morbidity ◽  
Review Of Literature ◽  
Cdh1 Gene ◽  
Preventative Measures ◽  
Cancer Review ◽  
Prophylactic Gastrectomy ◽  
Cdh1 Mutation

Summary Worldwide, gastric cancer is one of the most common forms of cancer, with a high morbidity and mortality. Both environmental and genetic factors have a role in the aetiology of gastric cancer. Familial clustering of gastric cancer is seen in 10-15% of cases, and approximately 3% of gastric cancer cases arise in the setting of hereditary diffuse gastric cancer ( HDGC). In families with HDGC, gastric cancer presents at relatively young age. Germline mutations in the CDH1 gene are the major cause of HDGC and are identified in approximately 25-40% of families which fulfill strict criteria. Prophylactic gastrectomy is the only option to prevent gastric cancer in individuals with a CDH1 mutation. However, in the majority of families with multiple cases of gastric cancer no germline genetic abnormality can be identified and therefore preventative measures are not available, except for general lifestyle advice. Future research should focus on identifying new genetic predisposing factors for all types of familial gastric cancer.

scholarly journals Hereditary diffuse gastric cancer: association with lobular breast cancer

2007 ◽  
Vol 7 (1) ◽  
pp. 73-82 ◽  
Author(s):  
Kasmintan A. Schrader ◽  
Serena Masciari ◽  
Niki Boyd ◽  
Sara Wiyrick ◽  
Pardeep Kaurah ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gastric Cancer ◽  
Hereditary Diffuse Gastric Cancer ◽  
Diffuse Gastric Cancer ◽  
Lobular Breast Cancer

scholarly journals Frequency of CDH1 Germline Mutations in Non-Gastric Cancers

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2321
Author(s):  
Giulia Massari ◽  
Francesca Magnoni ◽  
Giorgio Favia ◽  
Nickolas Peradze ◽  
Paolo Veronesi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gastric Cancer ◽  
Genetic Testing ◽  
Genetic Predisposition ◽  
Breast Tumors ◽  
Germline Mutations ◽  
Diffuse Gastric Cancer ◽  
Missense Mutations ◽  
Gastric Tumors ◽  
Cdh1 Mutation

Hereditary Diffuse Gastric Cancer (HDGC) is a complex inherited syndrome caused by CDH1 germline mutations. DGC is the hallmark cancer of this genetic predisposition, but several other cancers are associated with these CDH1 mutations. In this review, we revised all studies reporting CDH1 mutations in non-GC patients. The selected studies included: (a) families aggregating with GC and other cancers, both, and (b) families presenting only non-gastric tumors association. Among non-gastric tumors, our results show that CDH1 mutations are most frequently identified in breast cancer. The frequency of missense mutations is higher in the non-GC group, as the age at diagnosis in this group. Moreover, the predominant CDH1 mutation affects the extracellular domain. Our data suggest that CDH1 genetic testing should be considered also in other cancers, especially breast tumors.

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