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Hereditary diffuse gastric cancer (CTNNA1)
This rare genetic condition is associated with pathogenic variants in the CTNNA1 gene. Individuals with this condition have a higher chance of developing diffuse gastric cancer, which typically grows quickly and can be harder to detect early.
Overview
Hereditary diffuse gastric cancer (HDGC) is a rare inherited disorder primarily characterised by an increased lifetime risk of developing diffuse gastric cancer, a form of stomach cancer [PMID:33605634]. Unlike other types of stomach cancer, diffuse gastric cancer does not form a distinct mass but instead causes the stomach lining to thicken. This can make it challenging to detect in its early stages. The condition is passed down through families.
While diffuse gastric cancer is the main concern, some individuals with HDGC may also have an increased risk of developing lobular breast cancer [PMID:34426574]. Understanding the genetic basis of HDGC is crucial for identifying at-risk individuals and implementing appropriate screening and management strategies.
Symptoms & clinical features
Individuals with hereditary diffuse gastric cancer (CTNNA1) do not typically experience symptoms directly from the genetic variant itself. Instead, symptoms arise if and when cancer develops. Symptoms of diffuse gastric cancer can be vague and non-specific in the early stages, often including indigestion, nausea, vomiting, or a feeling of fullness after eating small amounts of food. As the cancer progresses, symptoms may include unexplained weight loss, abdominal pain, difficulty swallowing (dysphagia), or anaemia due to bleeding in the stomach.
Because diffuse gastric cancer can spread subtly through the stomach wall, these symptoms may not appear until the disease is more advanced. For those at risk due to a family history or known genetic variant, surveillance programmes aim to detect early changes before symptoms develop, improving treatment outcomes.
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Affected organs
The primary organ affected by hereditary diffuse gastric cancer (CTNNA1) is the stomach, where diffuse gastric cancer can develop. This type of cancer involves cells spreading throughout the stomach lining rather than forming a single tumour mass. This infiltration can lead to thickening and stiffening of the stomach wall.
Less commonly, some individuals with HDGC may also have an increased risk of developing lobular breast cancer, affecting the breast tissue. This highlights that the impact of pathogenic CTNNA1 variants can extend beyond the stomach in some cases [PMID:34426574].
Risks & severity
Hereditary diffuse gastric cancer associated with CTNNA1 is considered a rare condition, and the exact prevalence is not well established. Individuals with a pathogenic CTNNA1 variant have a significantly increased lifetime risk of developing diffuse gastric cancer, though specific risk percentages are still being refined through ongoing research [PMID:33605634]. The age of onset for gastric cancer in affected individuals can vary, but it often occurs at an earlier age compared to sporadic (non-inherited) gastric cancer.
The severity of the condition relates to the aggressive nature of diffuse gastric cancer, which can be challenging to treat once it has advanced. The prognosis is generally better with early detection and intervention. The risk of lobular breast cancer is also a consideration, particularly for women with a CTNNA1 variant.
Genetic causes
Hereditary diffuse gastric cancer (CTNNA1) is caused by pathogenic (disease-causing) variants in the CTNNA1 gene. This gene provides instructions for making a protein called alpha-E-catenin. Alpha-E-catenin plays a crucial role in cell adhesion, which is the process by which cells stick together to form tissues and organs.
Specifically, alpha-E-catenin is part of a complex that helps anchor cells together at specialised junctions called adherens junctions. These junctions are vital for maintaining the structural integrity of tissues, including the lining of the stomach. Pathogenic variants in CTNNA1 can disrupt the function of alpha-E-catenin, leading to impaired cell adhesion. This weakened adhesion is thought to contribute to the uncontrolled growth and spread characteristic of diffuse gastric cancer [PMID:33605634].
- CTNNA1 catenin alpha 1
Inheritance pattern
Hereditary diffuse gastric cancer (CTNNA1) is inherited in an autosomal dominant pattern. This means that only one altered copy of the CTNNA1 gene in each cell is enough to increase a person's risk of developing the condition. A person with a pathogenic CTNNA1 variant has a 50% chance of passing on the variant to each of their children, regardless of the child's sex.
Individuals who inherit the pathogenic variant may not necessarily develop cancer, but they will have a substantially increased lifetime risk. Family members of an affected individual can be offered genetic counselling and testing to determine if they also carry the variant and to discuss appropriate management options.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
Diagnosis of hereditary diffuse gastric cancer (CTNNA1) often begins with a strong family history of diffuse gastric cancer or lobular breast cancer. If there is a suspected genetic predisposition, individuals can be referred to a clinical genetics service in the UK. Genetic testing is then performed to identify pathogenic variants in the CTNNA1 gene.
Genetic testing for suspected hereditary gastric cancer syndromes falls under specific NHS Genomic Medicine Service (GMS) pathways, often linked to R-codes such as R189 Hereditary gastrointestinal cancers. This testing typically involves analysing a blood sample to look for changes in the CTNNA1 gene. Confirmation of a pathogenic variant helps to guide surveillance and management plans for the individual and their at-risk family members.
Management & lifestyle
Management for individuals with a pathogenic CTNNA1 variant focuses on surveillance and risk reduction strategies, tailored by a multidisciplinary team. For those identified through genetic testing, regular endoscopic surveillance of the stomach may be recommended to look for early signs of cancer [PMID:34426574]. The exact frequency and nature of surveillance are decided based on individual risk factors, family history, and clinical guidelines.
For some individuals, a risk-reducing total gastrectomy (surgical removal of the stomach) may be considered, particularly if close surveillance is difficult or if early cancerous changes are detected. This is a significant decision and is thoroughly discussed with patients and their families by clinical genetics teams, surgeons, and genetic counsellors. Women with CTNNA1 variants should also be aware of the increased risk of lobular breast cancer and discuss appropriate breast screening with their clinicians.
UK care pathway
In the UK, individuals suspected of having hereditary diffuse gastric cancer (CTNNA1) due to family history or clinical features will typically be referred to a Clinical Genetics service. This service is part of the NHS Genomic Medicine Service (GMS) and provides expert assessment, genetic counselling, and access to genetic testing. Testing for hereditary gastrointestinal cancer syndromes, including those related to CTNNA1, is covered by specific GMS R-codes (e.g., R189 Hereditary gastrointestinal cancers).
Genetic counsellors play a vital role, explaining the inheritance pattern, implications of testing for the individual and their family, and supporting decision-making regarding surveillance and risk management. Should a pathogenic variant be identified, care is then coordinated with relevant specialist teams, such as gastroenterologists, surgeons, and oncologists, to develop a personalised management plan.
Frequently asked questions
What is the difference between diffuse gastric cancer and other stomach cancers?
Diffuse gastric cancer grows differently from other stomach cancers. Instead of forming a visible lump, it spreads through the stomach lining, making the stomach wall thicker and stiffer. This can make it harder to detect early through standard endoscopy.
If I have a CTNNA1 variant, will I definitely get stomach cancer?
No, having a pathogenic CTNNA1 variant means you have a significantly increased lifetime risk of developing diffuse gastric cancer, but it does not mean you will definitely get it. Healthcare professionals will discuss your specific risks and recommend surveillance or risk-reducing options.
Can men also be affected by CTNNA1-related hereditary diffuse gastric cancer?
Yes, because hereditary diffuse gastric cancer (CTNNA1) is inherited in an autosomal dominant pattern, both men and women have an equal chance of inheriting the pathogenic variant and are at increased risk of developing diffuse gastric cancer. Women may also have an increased risk of lobular breast cancer.
What kind of surveillance would I have if I have a CTNNA1 variant?
Surveillance typically involves regular endoscopic examinations (gastroscopies) to carefully examine the stomach lining for any early changes. The frequency and specific methods of surveillance will be determined by your clinical team based on current guidelines and your individual circumstances.
Are there other cancers associated with CTNNA1 variants?
While diffuse gastric cancer is the primary concern, some research suggests an increased risk of lobular breast cancer in individuals with pathogenic CTNNA1 variants. If you have a CTNNA1 variant, your clinical team will discuss any other potential cancer risks with you.