Hereditary Diffuse Gastric CancerEdit
Hereditary Diffuse Gastric Cancer (HDGC) is a hereditary cancer syndrome that markedly increases the lifetime risk of developing diffuse gastric cancer. It most commonly arises from pathogenic variants in the CDH1 gene, which encodes the cell-adhesion protein E-cadherin. In a subset of families, other genes such as CTNNA1 have also been implicated. The condition is inherited in an autosomal dominant pattern, and penetrance varies among families, making genetic testing and personalized risk management central to care. A distinguishing feature of HDGC is the diffuse, insidious spread of cancer through the stomach wall, often with signet-ring cell histology, which can complicate early detection and treatment. In women who carry CDH1 variants, there is also an elevated risk of lobular breast cancer, which shapes broader surveillance and management decisions.
HDGC is characterized by a high lifetime risk of diffuse-type gastric cancer, rather than the more common intestinal-type gastric cancers. The disease often presents as a hidden, infiltrative process that can progress with relatively subtle symptoms until advanced stages. The cancer cells frequently show signet-ring morphology, and the pattern of growth—spreading through the stomach wall—can lead to a condition known as linitis plastica. Because these cancers can originate beneath the mucosal surface, routine endoscopic screening can miss early disease, underscoring the importance of genetic risk assessment and, in many cases, risk-reducing strategies. The syndrome also raises considerations for relatives, given the autosomal dominant inheritance and variable penetrance across families.
Genetic basis
The CDH1 gene is the major genetic determinant of HDGC. Mutations that impair E-cadherin function disrupt cell–cell adhesion, enabling diffuse infiltration of the stomach lining by cancerous cells. In addition to CDH1 mutations, pathogenic variants in CTNNA1 have been associated with HDGC in some families, illustrating that the syndrome can arise from disruption of the broader adherens junction complex. Inheritance is autosomal dominant, meaning a single mutated copy can confer substantial risk to offspring, though the level of risk (penetrance) varies by family and age.
Penetrance estimates for CDH1-related HDGC are high but not absolute. By some accounts, the lifetime risk of developing gastric cancer by age 80 is on the order of about 70% for men and somewhat lower for women, with substantial uncertainty depending on family history and other modifiers. Women who carry CDH1 mutations also face an elevated risk of lobular breast cancer, contributing to the overall cancer burden in mutation carriers. The discovery and confirmation of CDH1’s role in HDGC emerged from collaborative work by multiple research consortia and clinical centers, including the IGCLC and national cancer research programs, which have shaped contemporary testing criteria and management guidelines.
Clinical features and diagnosis
HDGC typically presents as a familial cluster of gastric cancers that may occur at younger ages than sporadic cases. The defining intestinal histology is often not evident on a single biopsy because the malignancy can spread submucosally. As a result, individuals with a known pathogenic variant or a strong family history are managed with a combination of genetic testing, surveillance, and risk-reducing surgical strategies rather than relying solely on standard endoscopic detection.
In females with pathogenic CDH1 variants, the risk of lobular breast cancer is a key component of the clinical picture, guiding broader surveillance for breast cancer alongside gastric cancer risk management.
Genetic testing and counseling
Genetic testing for HDGC is guided by established criteria that consider personal and family history of diffuse gastric cancer, early-onset gastric cancer, and lobular breast cancer in female relatives. When a pathogenic or likely pathogenic CDH1 variant is identified, cascade testing of at-risk relatives is typically offered. Counseling covers the implications of test results, the autosomal dominant inheritance pattern, cancer risks, and the range of management options. The decision to pursue testing and subsequent interventions is highly individualized and involves consideration of quality of life, personal preferences, and family planning goals.
Testing for CTNNA1 and other potential HDGC-associated genes may be offered in research or specialized clinical settings as more data accumulate on penetrance and cancer risk.
Management and prevention
For CDH1 mutation carriers, the principal clinical decision is often whether to pursue risk-reducing surgery versus intensive endoscopic surveillance. Prophylactic or risk-reducing total gastrectomy is a major operation with lifelong nutritional consequences, but it can dramatically reduce the risk of developing gastric cancer in HDGC. The timing of surgery is individualized, commonly discussed with reference to age, family history, and the patient’s tolerance for potential postoperative side effects. In many centers, prophylactic gastrectomy is considered in adulthood, with some families choosing earlier intervention to mitigate cancer risk given the high penetrance estimates.
When surgery is deferred or not undertaken, endoscopic surveillance is used, typically involving repeated upper endoscopies with multiple biopsies from various stomach regions. However, endoscopic surveillance has limitations in detecting early HDGC due to the diffuse growth pattern, making risk-reducing surgery a central option for many carriers.
Postoperative care after gastrectomy focuses on nutrition, weight maintenance, and prevention of deficiencies (such as vitamin B12 and other micronutrients). Patients require long-term follow-up with dietitians and metabolic specialists to adjust to the altered digestive tract.
For female CDH1 mutation carriers, surveillance for breast cancer—most notably annual or semiannual modalities for lobular breast cancer—is commonly recommended as part of a comprehensive risk-management plan.
Controversies and debates
The HDGC literature reflects ongoing debates about the optimal balance between surveillance and surgery, the precise lifetime risk estimates for different gene carriers, and the best strategies for family members. Critics of aggressive prophylactic surgery emphasize the potential impact on quality of life, nutritional status, and the psychological burden of a major operation, arguing for more nuanced, staged approaches or intensified endoscopic surveillance in selected cases. Proponents of early surgical risk reduction stress the high penetrance and the difficulty of reliable early detection with endoscopy, arguing that timely gastrectomy can prevent metastatic spread and improve long-term survival.
There is also discussion about the appropriate scope of genetic testing, including when to offer testing to relatives and how to manage incidental or unclear findings. Additionally, the emergence of risk for lobular breast cancer in female carriers broadens the conversation to multidisciplinary cancer surveillance and the allocation of healthcare resources, particularly in settings with constrained access to specialized surgical and nutritional care.
Care decisions in HDGC are deeply personal and often involve weighing long-term lifestyle changes against the relative certainty of cancer risk reduction. The evolving understanding of penetrance, genotype–phenotype correlations, and the psychosocial implications of treatment options continues to shape guidelines issued by expert groups such as the IGCLC and national cancer institutes.