Hereditary diffuse gastric cancer: association with lobular breast cancer

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.

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CDH-1 germ line mutations in diffuse gastric and infiltrating ductal breast cancer

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e22218 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e22218-e22218

Author(s):

A. P. Efremidis ◽

F. Fostira ◽

C. Panopoulos ◽

K. Papademitriou ◽

N. Pistalmazian ◽

...

Keyword(s):

Breast Cancer ◽

Gastric Cancer ◽

Positive Family History ◽

Bilateral Breast Cancer ◽

Hereditary Diffuse Gastric Cancer ◽

Bilateral Mastectomy ◽

Diffuse Gastric Cancer ◽

Cancer Type ◽

Diffuse Type ◽

Cdh1 Gene

e22218 Background: Hereditary Diffuse Gastric Cancer (HDGC) syndrome is characterized by the predisposition to gastric cancer of the diffuse type and to breast cancer of the lobular type. The autosomal dominantly inherited germline mutations of the E- cadherin (CDH1) gene are the defects underlying the HDGC syndrome. The median age of onset for diffuse gastric cancer is 38 years. CDH1 mutations are highly penetrant, conferring a cumulative risk of diffuse gastric cancer of 75%. Methods: Genomic DNA was purified from peripheral blood leukocytes following standard chloroform extraction. The complete coding sequences of the CDH1-gene, including splice junctions, were amplified by Polymerase Chain Reaction (PCR) and electrophorized in an ABI Prism 310 Genetic Analyzer. Results: A pathogenic mutation located on exon 7 of the CDH1 gene was identified in a female patient diagnosed with bilateral breast cancer at the age of 36. She underwent bilateral mastectomy for an infiltrating ductal adenocarcinoma of the left breast and in situ lobular of the right breast. At the age of 45 the patient underwent gastrectomy for diffuse type gastric adenocarcinoma. She had a positive family history for breast and gastric cancer from both sides, but without meeting the absolute clinical criteria for hereditary diffuse gastric cancer syndrome. The nonsense mutation found was probably maternally inherited, since the maternal grandmother was diagnosed with breast cancer at the age of 38. Conclusions: The selection process of patients for genetic testing for the HDGC syndrome is not quite clear at the moment, as it is apparent that more types of breast cancer and not only lobular, can be associated with the syndrome. Criteria should be more flexible in respects to the histopathology of the cancer type. This is the first CDH1 mutation identified in a Greek patient. No significant financial relationships to disclose.

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Hereditary diffuse gastric cancer and lynch syndromes in a BRCA1/2 negative breast cancer patient

Breast Cancer Research and Treatment ◽

10.1007/s10549-017-4393-3 ◽

2017 ◽

Vol 166 (1) ◽

pp. 315-319 ◽

Cited By ~ 3

Author(s):

Scolastica W. Njoroge ◽

Kelly R. Burgess ◽

Melody A. Cobleigh ◽

Hussein H. Alnajar ◽

Paolo Gattuso ◽

...

Keyword(s):

Breast Cancer ◽

Gastric Cancer ◽

Cancer Patient ◽

Breast Cancer Patient ◽

Hereditary Diffuse Gastric Cancer ◽

Diffuse Gastric Cancer

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

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.4_suppl.16 ◽

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.

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Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse gastric cancer families

Gastroenterology ◽

10.1053/gast.2001.29611 ◽

2001 ◽

Vol 121 (6) ◽

pp. 1348-1353 ◽

Cited By ~ 372

Author(s):

Paul D.P. Pharoah ◽

Parry Guilford ◽

Carlos Caldas

Keyword(s):

Breast Cancer ◽

Gastric Cancer ◽

Hereditary Diffuse Gastric Cancer ◽

Diffuse Gastric Cancer ◽

Mutation Carriers ◽

E Cadherin

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Associations of CDH1 germline variant location and cancer phenotype in families with hereditary diffuse gastric cancer (HDGC)

Journal of Medical Genetics ◽

10.1136/jmedgenet-2018-105361 ◽

2019 ◽

Vol 56 (6) ◽

pp. 370-379 ◽

Cited By ~ 10

Author(s):

Winifred Lo ◽

Bin Zhu ◽

Arvind Sabesan ◽

Ho-Hsiang Wu ◽

Astin Powers ◽

...

Keyword(s):

Breast Cancer ◽

Colorectal Cancer ◽

Gastric Cancer ◽

Young Age ◽

Hereditary Diffuse Gastric Cancer ◽

Diffuse Gastric Cancer ◽

Germline Variants ◽

Germline Variant ◽

Increased Risk ◽

E Cadherin

IntroductionHereditary diffuse gastric cancer (HDGC) is a cancer syndrome associated with variants in E-cadherin (CDH1), diffuse gastric cancer and lobular breast cancer. There is considerable heterogeneity in its clinical manifestations. This study aimed to determine associations between CDH1 germline variant status and clinical phenotypes of HDGC.MethodsOne hundred and fifty-two HDGC families, including six previously unreported families, were identified. CDH1 gene-specific guidelines released by the Clinical Genome Resource (ClinGen) CDH1 Variant Curation Expert Panel were applied for pathogenicity classification of truncating, missense and splice site CDH1 germline variants. We evaluated ORs between location of truncating variants of CDH1 and incidence of colorectal cancer, breast cancer and cancer at young age (gastric cancer at <40 or breast cancer <50 years of age).ResultsFrequency of truncating germline CDH1 variants varied across functional domains of the E-cadherin receptor gene and was highest in linker (0.05785 counts/base pair; p=0.0111) and PRE regions (0.10000; p=0.0059). Families with truncating CDH1 germline variants located in the PRE-PRO region were six times more likely to have family members affected by colorectal cancer (OR 6.20, 95% CI 1.79 to 21.48; p=0.004) compared with germline variants in other regions. Variants in the intracellular E-cadherin region were protective for cancer at young age (OR 0.2, 95% CI 0.06 to 0.64; p=0.0071) and in the linker regions for breast cancer (OR 0.35, 95% CI 0.12 to 0.99; p=0.0493). Different CDH1 genotypes were associated with different intracellular signalling activation levels including different p-ERK, p-mTOR and β-catenin levels in early submucosal T1a lesions of HDGC families with different CDH1 variants.ConclusionType and location of CDH1 germline variants may help to identify families at increased risk for concomitant cancers that might benefit from individualised surveillance and intervention strategies.

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