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Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant hereditary cancer syndrome that increases an individual's risk to develop diffuse gastric cancer and lobular breast cancer. HDGC is defined by the presence of germline pathogenic variants in the CDH1 gene, which codes for the cell–cell adhesion junction protein, E-cadherin. In CDH1 pathogenic variant carriers, lifetime risk of diffuse gastric cancer (to age 80 y) ranges from 37% to 70% in men and 25% to 83% in women.[
Pathogenic variants in a second gene, CTNNA1, are found in a small number of families with HDGC. This gene codes for an adhesion junction protein, alpha-E-catenin.[
References:
The International Gastric Cancer Linkage Consortium's (IGCLC) 2020 HDGC genetic testing guidelines are summarized below.[
When an individual meets HDGC genetic testing criteria but genetic testing does not reveal a CDH1pathogenic variant, CTNNA1 genetic testing is recommended.
Personal History Criteria
Family History Criteria a
a Family members must be FDRs or second-degree relatives of each other. The IGCLC recommends that affected family members undergo genetic testing, when possible. Providers may want to consider testing tissue (tumor tissue or healthy tissue) from deceased, affected relatives if a family does not have living individuals with breast or gastric cancers. If none of these options are feasible, providers can consider performing genetic testing in unaffected family members. Diffuse gastric cancer is generally diagnosed at an advanced stage (i.e., stage III or stage IV).[
References:
CDH1germline pathogenic variants are found in 30% to 40% of families with clinically defined HDGC from different ethnic backgrounds.[
In HDGC-like families, affected individuals and their FDRs may be considered for yearly endoscopic surveillance for at least 2 years after receiving a negative CDH1 genetic test result.[
References:
Hereditary diffuse gastric cancer (HDGC) was first identified in a large, indigenous Māori kindred from New Zealand. These individuals had a germline pathogenic variant in the CDH1gene. [
Molecular Biology
In 1995, the CDH1 (cadherin-1) gene was mapped to chromosome 16q22.1.[
Genotype-Phenotype Correlations
CDH1 pathogenic variants demonstrate considerable heterogeneity with the types of cancers and the ages of cancer onset seen in carriers. However, a review of available CDH1 literature from 1985 to 2018 did not definitively establish genotype -phenotype correlations that could help direct patient management. This review found that CDH1 pathogenic variants are evenly distributed throughout the gene without a preferential variant type (i.e., nonsense, missense, etc.) or location.[
Possible CDH1 genotype-phenotype correlations have been observed in families with HDGC and cleft lip or cleft palate. However, it is unclear which CDH1 pathogenic variants lead to cleft lip or cleft palate. In 2006, CDH1 splice site variants were found in two families with HDGC and cleft lip or cleft palate. The splice site variants resulted in complex, aberrant splicing in lymphocytes.[
The term, hereditary lobular breast cancer, was created by the International Gastric Cancer Linkage Consortium to describe individuals with a CDH1 pathogenic variant and personal/family histories of lobular breast cancer, but no known personal/family histories of gastric cancer.[
Overall, there are insufficient data regarding possible CDH1 genotype-phenotype correlations. These findings are not substantial enough to guide individualized CDH1 cancer risk assessment and management.
References:
Gastric Cancer Risk
In CDH1pathogenic variant carriers, lifetime risk of diffuse gastric cancer (to age 80 y) ranges from 37% to 70% in men and 25% to 83% in women.[
Figure 1. High-power image of a gastric biopsy tissue sample showing signet ring cell carcinoma. Note the absence of gland formation, which indicates that this lesion is poorly-differentiated carcinoma. Also note the overlying epithelium, which although effaced by the presence of underlying tumor, is otherwise normal.
Figure 2. Endoscopic image of diffuse gastric cancer with typical linitis plastica involvement. This occurs at an advanced stage. The gastric mucosa and submucosa are diffusely infiltrated such that the entire stomach becomes stiff, losing contractility and the ability to digest food. This leads to the typical symptoms of nausea and vomiting. Biopsy is generally informative, but a very superficial biopsy may be negative for cancer cells. Hence, it is imperative for pathologists to carefully search biopsy specimens for isolated signet ring cells.
Breast Cancer Risk
In the general population, most breast cancers are ductal, while about 10% are lobular.[
References:
Surgical Intervention: Risk-Reducing Gastrectomy
Risk-reducing total gastrectomy with esophagojejunostomy remains the treatment of choice for individuals with CDH1pathogenic variants.[
Functional outcomes after risk-reducing total gastrectomy vary, but weight loss is universal. One series reported an average weight loss of 15% to 20% postsurgery.[
Endoscopic Surveillance
Risk-reducing total gastrectomy is the treatment of choice for patients with hereditary diffuse gastric cancer (HDGC) because it is the only way to minimize gastric cancer risk, given the lack of consistently identifiable precursor lesions on endoscopy.[
More recently, researchers performed surveillance EGDs on 20 CDH1 carriers.[
There is a role for endoscopic surveillance in HDGC, particularly for patients who choose to defer risk-reducing total gastrectomy. Other scenarios that may prompt endoscopic surveillance include the following:[
There are no definitive, identifiable features of early diffuse gastric cancer or diffuse gastric cancer precursors that can be found on endoscopy. Hence, a liberal number of random biopsies are taken from the gastric mucosa during endoscopy since the epithelium that covers signet ring cell carcinoma generally appears normal. Early reports suggested that individuals with HDGC can have many microscopic tumors in the body-antrum transitional zone.[
Several studies have suggested that small, white plaques in the stomach may signify that an underlying signet ring cell carcinoma focus is present. Biopsying these white plaques may improve endoscopic yield.
Figure 3. Several small, white, slightly depressed areas are best seen with narrow-band imaging. These lesions can resemble scars from previous endoscopic biopsies. However, the images above are from a patient who did not have a prior esophagogastroduodenoscopy. A microscopic signet ring cell carcinoma focus was found on this biopsy, although nontargeted biopsies in this patient were also positive for signet ring cell carcinoma.
Another study reported on 33 patients with CDH1 pathogenic variants (median age, 32 y) who were members of the original Māori family in which HDGC was first discovered. Participants underwent 99 surveillance endoscopies, 93 of which were performed with a mucolytic N-acetylcysteine followed by Congo red–methylene blue dye.[
If an endoscopic approach is taken for HDGC management, endoscopic surveillance is recommended annually unless signet ring cell features are found. If signet ring cell lesions are found on endoscopy, discussion with a multidisciplinary team is warranted.[
Breast Cancer Risk Management
In females with a CDH1 pathogenic variant, screening modalities for breast cancer include the following:
Breast magnetic resonance imaging (MRI):
Mammography:
Other imaging:
Bilateral risk-reducing mastectomy can be considered for women with a CDH1 pathogenic variant based on a strong family history of breast cancer, additional breast cancer risk factors, and/or personal choice.[
References:
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Management
Added Breast Cancer Risk Management as a new subsection.
This summary is written and maintained by the PDQ Cancer Genetics Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of hereditary diffuse gastric cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
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Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Hereditary Diffuse Gastric Cancer are:
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PDQ® Cancer Genetics Editorial Board. PDQ Hereditary Diffuse Gastric Cancer. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/about-cancer/causes-prevention/genetics/hereditary-diffuse-gastric-cancer-hp-pdq. Accessed <MM/DD/YYYY>.
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Last Revised: 2023-11-09
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