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Hereditary diffuse gastric cancer
HDGC is a rare genetic condition primarily affecting the stomach and breasts. It is caused by changes in certain genes, most commonly CDH1, leading to a much higher chance of developing specific cancers during an individual's lifetime. Understanding this condition is crucial for early detection and management.
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Overview
Hereditary diffuse gastric cancer (HDGC) is a genetic disorder characterised by a significantly increased risk of developing diffuse type gastric cancer (DGC) and, in women, lobular breast cancer (LBC) [PMID:32250106]. DGC is a particularly aggressive form of stomach cancer that can be challenging to detect early due to its growth pattern. Unlike other types of stomach cancer, DGC does not typically form a distinct mass but spreads subtly within the stomach lining. HDGC is considered a rare condition, and individuals with this diagnosis often require specialised management and surveillance strategies.
Symptoms & clinical features
Individuals with HDGC generally do not experience specific symptoms that would alert them to the presence of diffuse gastric cancer in its early stages. This lack of early warning signs is a key challenge in managing the condition, as the cancer can progress undetected. When symptoms do appear, they are often non-specific and may include indigestion, unexplained weight loss, abdominal pain, difficulty swallowing, or nausea. These symptoms typically indicate more advanced disease. For lobular breast cancer associated with HDGC, symptoms can include a new lump or thickening in the breast, changes in breast size or shape, or nipple alterations [PMID:31992019].
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Affected organs
The primary organ affected by HDGC is the stomach, where diffuse type gastric cancer develops. This type of cancer involves the inner lining of the stomach and can spread widely without forming a discrete tumour. The cells tend to infiltrate the stomach wall, making it thick and rigid. In women, the breasts are also significantly affected, with an increased risk of developing lobular breast cancer. There is also some evidence suggesting a possible increased risk for other cancers, but this is less well-established compared to gastric and breast cancers [PMID:27092284].
Risks & severity
HDGC is associated with a substantially increased lifetime risk of developing diffuse gastric cancer for both men and women. For women, there is also a significantly increased lifetime risk of lobular breast cancer. The severity of HDGC stems from the aggressive nature of diffuse gastric cancer and the difficulty in detecting it early. Without appropriate surveillance and risk-reducing strategies, the prognosis for advanced gastric cancer is generally poor.
Genetic causes
HDGC is most commonly caused by pathogenic variants in the CDH1 gene. This gene provides instructions for making a protein called E-cadherin. E-cadherin is crucial for cell-to-cell adhesion, acting as a 'glue' that holds epithelial cells together and helps maintain tissue structure throughout the body, including the stomach lining. It also plays a role in cell signalling and differentiation, processes vital for normal cell growth and development. Pathogenic variants in CDH1 can lead to a dysfunctional E-cadherin protein or prevent its production altogether. When E-cadherin function is impaired, cells may lose their normal adhesion, allowing them to detach and spread more easily, which contributes to the development of diffuse gastric cancer and lobular breast cancer.
- CDH1 cadherin 1The CDH1 gene provides instructions for producing the E-cadherin protein, which is crucial for cell adhesion, tissue organisation, and acts as a tumour suppressor.
Inheritance pattern
HDGC follows an autosomal dominant inheritance pattern. This means that if an individual has one copy of a pathogenic variant in a gene like CDH1, they will have the condition and the associated cancer risks. Each child of an affected parent has a 50% chance of inheriting the pathogenic variant. The condition affects males and females equally, although the specific cancer risks vary between sexes (e.g., only women are at risk of lobular breast cancer). Individuals who inherit the variant may not necessarily develop cancer, but they have a significantly increased predisposition.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
Diagnosis of HDGC often begins with a strong family history of diffuse gastric cancer, especially at young ages, or multiple cases of lobular breast cancer. The definitive diagnosis is confirmed through genetic testing to identify pathogenic variants, typically in the CDH1 gene. In the UK, genetic testing for HDGC is usually accessed through the NHS Genomic Medicine Service (GMS) via a referral to a Clinical Genetics service. Clinical Genetics teams assess family history and clinical features to determine if testing is appropriate. The relevant R-code for HDGC genetic testing is usually R197. Genetic counselling is an integral part of the diagnostic process, providing information and support to individuals and families considering testing [PMID:35777176].
Management & lifestyle
Management of HDGC involves a comprehensive and personalised approach focused on surveillance and risk reduction. For individuals with a confirmed CDH1 pathogenic variant, prophylactic total gastrectomy (surgical removal of the entire stomach) is typically recommended to prevent diffuse gastric cancer. The timing of this major surgery is discussed with a multidisciplinary team based on individual circumstances and family history. Women with a CDH1 pathogenic variant are also advised to undergo regular breast screening, often with MRI, due to the increased risk of lobular breast cancer. Risk-reducing bilateral mastectomy may also be considered. Surveillance and management strategies are discussed within the NHS Genomic Medicine Service pathway and guided by clinical genetics specialists and genetic counsellors. Lifestyle modifications, while not preventing HDGC, can generally support overall health.
UK care pathway
In the UK, individuals suspected of having HDGC, or those with a confirmed diagnosis, are managed through the NHS Genomic Medicine Service (GMS). This pathway typically begins with a referral to a Clinical Genetics service. Here, a genetic counsellor or clinical geneticist will assess family history and clinical presentation to determine the appropriateness of genetic testing, often using the R-code R197 for HDGC. Genetic counselling is provided throughout this process, offering crucial information, support, and guidance regarding inheritance, cancer risks, and management options. Multidisciplinary teams, including surgeons, oncologists, and gastroenterologists, work together to provide coordinated care.
Frequently asked questions
What is the difference between hereditary diffuse gastric cancer and other stomach cancers?
Hereditary diffuse gastric cancer (HDGC) is a specific type of stomach cancer that is inherited, typically caused by changes in the CDH1 gene. It grows differently from other stomach cancers, spreading subtly within the stomach lining rather than forming a distinct mass, making it harder to detect early.
If I have HDGC, will I definitely get stomach cancer?
No, having HDGC means you have a significantly increased lifetime risk of developing stomach cancer, but it is not a certainty. This increased risk is why proactive management and surveillance are so important.
What are the options for managing the risk of stomach cancer with HDGC?
The main option for managing the risk of stomach cancer with HDGC is a prophylactic total gastrectomy, which is the surgical removal of the entire stomach before cancer develops. Regular surveillance with endoscopies is also an option for some, but it is less effective for detecting diffuse type gastric cancer.
Is lobular breast cancer also a risk with HDGC?
Yes, women with HDGC have a significantly increased lifetime risk of developing lobular breast cancer. Regular breast screening, often with MRI, and sometimes risk-reducing mastectomy, are recommended for women with a CDH1 pathogenic variant.
How can my family members find out if they are at risk?
Since HDGC is an inherited condition, once a pathogenic variant is identified in a family, other at-risk relatives can undergo genetic testing. This is typically arranged through a Clinical Genetics service and involves genetic counselling to discuss the implications of testing.
References
- Blair VR, McLeod M, Carneiro F. Hereditary diffuse gastric cancer: updated clinical practice guidelines. The Lancet. Oncology. 2020. PMID: 32758476
- Decourtye-Espiard L, Guilford P. Hereditary Diffuse Gastric Cancer. Gastroenterology. 2023. PMID: 36740198
- Hansford S, Kaurah P, Li-Chang H. Hereditary Diffuse Gastric Cancer Syndrome: CDH1 Mutations and Beyond. JAMA oncology. 2015. PMID: 26182300
- Ryan CE, Fasaye GA, Gallanis AF. Germline CDH1 Variants and Lifetime Cancer Risk. JAMA. 2024. PMID: 38873722
- Gullo I, Grillo F, Mastracci L. Precancerous lesions of the stomach, gastric cancer and hereditary gastric cancer syndromes. Pathologica. 2020. PMID: 33179620
- Hata K, Yamamoto Y, Kiyomatsu T. Hereditary gastrointestinal cancer. Surgery today. 2016. PMID: 26676416
- Carneiro F. Hereditary gastric cancer. Der Pathologe. 2012. PMID: 23052347
- Banks M, Graham D, Jansen M. British Society of Gastroenterology guidelines on the diagnosis and management of patients at risk of gastric adenocarcinoma. Gut. 2019. PMID: 31278206