Diffuse Gastric and Lobular Breast Cancer Syndrome
Diffuse Gastric and Lobular Breast Cancer Syndrome (DGLBC: ORPHA:26106, OMIM: 137215), previously known as Hereditary Diffuse Gastric Cancer (HDGC), is a cancer-associated syndrome characterized by the development of stomach cancer in both males and females, and breast cancer in females, before the age of 50 years. It is predicted to have a population incidence of 5-10 cases per 100,000 births. Only particular subtypes of stomach and breast cancer occur in DGLBC families: diffuse-type stomach cancer and lobular-type breast cancer. Stomach cancer is the most frequent cancer type in these families, and occurs in general earlier than breast cancer and leads to cancer-related death. Breast cancer is the second most frequent type of cancer. In some families with stomach and or breast cancer, cleft-lip with or without cleft-palate recurrently occur. Families may present with stomach cancer only, breast cancer only or both cancer types. Successive generations are commonly affected by these tumour types, and cancer onset is frequent in people in their 20s or 30s, but may also occur earlier. Diffuse-type stomach cancer or lobular-type breast cancer may occur in isolated patients, who do not report family history, and before 50 years of age.
DGLBC is caused by a genetic defect in one of the following genes: CDH1 and CTNNA1. These genetic defects are inherited within families and transmitted from generation to generation. Both genes (E-cadherin and alpha-E-catenin, respectively) produce proteins that are essential to keep the integrity and structure of epithelia and to maintain cell to cell adhesion. This is the reason why loss of function of any of these genes cause diffuse-type gastric cancer and lobular-type breast cancer, which are cancers without cell-to-cell adhesion that can migrate and invade adjacent tissues and organs. The CDH1 gene is the most frequently affected gene in DGLBC families, and only ‘Likely pathogenic’ or ‘Pathogenic’ variants in CDH1 cause DGLBC. Depending on the geographical origin of families, it is expected that 10 to 40% of families fulfilling clinical criteria (ERN GENTURIS endorsed guideline: Vanessa R Blair et al. Hereditary diffuse gastric cancer: updated clinical practice guidelines. Lancet Oncology (Aug 2020); 21(8): e386-e397) for this disease will carry a CDH1 disease-causing variant.
HDGC may also be caused by variants in the CTNNA1 gene. Current data supports an association of loss of function CTNNA1 variants with diffuse-type gastric cancer, but data is still scarce to demonstrate an association with lobular-type breast cancer.
DGLBC is an autosomal dominant syndrome, meaning that all family generations tend to have affected individuals with stomach cancer, breast cancer, or both. Individuals inheriting a single copy of the mutant gene (CDH1 or CTNNA1) are at increased risk to develop any of the cancers above. The mutant gene copy is inherited, not the disease itself.
Both men and women carrying a mutant copy of CDH1 (proven disease causative) have more than 50% risk of developing gastric cancer or breast cancer by 80 years of age. Women have a further 50% risk of developing lobular breast cancer at the same age. The probability of developing any of these cancers or both, by the age of 80, is considerably higher for women than for men.
If a CDH1 or CTNNA1 disease causing variant has been detected within a family, close follow-up is necessary and healthy relatives can be offered predictive testing from the age of 18 years for the disease-causing gene variant.
Preimplantation and prenatal genetic testing may be discussed with the clinical team.
Individuals at risk, meaning first- and second-degree relatives of an affected person carrying the disease-causing variant, should attend medical genetics appointments. In these appointments, patients will receive genetic counselling and genetic testing will be performed. Family members who are found to carry the disease causal variant will enter a clinical pathway of care, where adequate clinical care and follow-up is provided by a multidisciplinary expert team.
The primary disease preventive option is removal of the stomach (total gastrectomy) in people who carry the disease-causing variant, despite lacking symptoms of disease. In case gastrectomy is not appropriate, surveillance can be completed with yearly gastroscopy with endoscopy and multiple biopsies, in centres with expertise in this disease. Risk-reduction gastrectomy is broadly recommended to CDH1-variant carriers, even if cancer is not found in a surveillance biopsy. For CTNNA1-variant carriers with family or personal history of diffuse gastric cancer, risk-reduction gastrectomy is recommended, if a positive biopsy is found during surveillance. In CTNNA1-variant carrier families lacking family history of stomach cancer, preventive surgery is recommended only if a cancer-positive biopsy is found during surveillance.
Yearly bilateral breast magnetic resonance imaging (MRI) with contrast is recommended in CDH1-variant female carriers, starting at age 30 years. From age 40 and between MRI screens, annual mammography combined with ultrasound is recommended through a high-risk breast-screening program. This is the most adequate screening procedure for early detection of lobular breast cancer. Breast surgery is offered to patients presenting early breast cancer lesions and is generally curative. The preventive removal of both breasts, even if early lesions are not found, is also an option and should be carefully discussed with the patient and the clinical team. For CTNNA1-variant carriers breast surveillance and preventive surgery should be discussed based on family history of this disease.
Endorsed guidelines for other genturis - Hereditary diffuse gastric cancer: updated clinical practice guidelines
* ERN GENTURIS uses AGREE II as a tool for the endorsement of guidelines. The quality of the guideline is evaluated through assessing the rigor and transparency of the guideline development process. The content of the guideline is not evaluated, although selection of the guideline for endorsement includes expert opinion on the usefulness of the content of the guideline.
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Thematic Group 4: Other rare – predominantly malignant – genturis
Diffuse Gastric and Lobular Breast Cancer Syndrome (DGLBC)
A list of healthcare providers with expertise in Thematic Group 4: Other rare - predominantly malignant - genturis can be found here.
A non-exhaustive list of patient associations for genetic tumour risk syndromes in EU member states can be found here.