Hereditary Diffuse Gastric Cancer: Symptoms, Types, Causes and Treatment

Hereditary Diffuse Gastric Cancer (HDGC) is a rare but aggressive inherited cancer syndrome that profoundly impacts families carrying certain gene mutations. Understanding HDGC is crucial for early diagnosis, risk assessment, and management. This article presents a comprehensive overview of HDGC, focusing on its symptoms, types, causes, and available treatment options, guided by the latest evidence and clinical guidelines.

Symptoms of Hereditary Diffuse Gastric Cancer

HDGC is notorious for its subtle and often silent clinical presentation, especially in its early stages. Because the cancer develops in a diffuse pattern, traditional warning signs may be absent until the disease is advanced. Awareness of both common and less typical symptoms is essential for at-risk individuals and clinicians alike.

Symptom	Frequency	Typical Stage	Source(s)
Nonspecific GI symptoms	Common	Advanced	1, 6, 11
Epigastric pain	Sometimes	Advanced	6, 11
Weight loss	Common	Advanced	6, 11
Nausea/vomiting	Sometimes	Advanced	6
Early satiety	Sometimes	Advanced	6
Asymptomatic (microscopic lesions)	Very common	Early (T1a, mucosal)	1, 5, 11

Table 1: Key Symptoms

Early and Subtle Manifestations

• Microscopic Lesions: In HDGC, especially in CDH1 mutation carriers, the disease often begins as multiple microscopic foci of signet ring cell carcinoma scattered throughout the stomach lining. These early lesions are usually asymptomatic and can persist for years without causing any noticeable signs 1 5 11.
• Absence of Early Symptoms: Most carriers are completely symptom-free in the initial stages, which makes early detection challenging without proactive genetic and endoscopic screening 5 6 11.

Progression to Overt Disease

• Nonspecific GI Complaints: As the cancer advances, individuals may experience vague gastrointestinal symptoms, such as mild abdominal discomfort, indigestion, or a sensation of fullness after eating small amounts (early satiety). These symptoms are common to many benign conditions, which often leads to delays in diagnosis 6 11.
• Weight Loss and Pain: Unintended weight loss, persistent epigastric pain, and vomiting may occur as the disease progresses and begins to invade deeper layers of the stomach or causes gastric outlet obstruction 6.
• Other Signs: Less commonly, patients might present with anemia due to occult bleeding, or more pronounced symptoms if the disease spreads beyond the stomach.

Importance of Surveillance

Given the indolent nature of early HDGC and the lack of specific symptoms, regular surveillance in high-risk individuals (CDH1/CTNNA1 mutation carriers and those with strong family history) is recommended for early detection 5 8 11.

Types of Hereditary Diffuse Gastric Cancer

HDGC is not a single entity but a spectrum with distinct clinical and histological features. Understanding its subtypes and related syndromes helps tailor risk assessment and management strategies.

Type/Subtype	Features	Genetics	Source(s)
Classic HDGC	Diffuse gastric cancer, signet ring cells	CDH1 mutations	2, 3, 6, 7
HDGC-like	Meets clinical criteria, no known mutation	Unknown	2, 8, 9
Hereditary Lobular Breast Cancer (HLBC)	Lobular breast cancer only	CDH1 mutations	2, 8
CDH1-negative HDGC	Diffuse gastric cancer, familial, no CDH1 mutation	CTNNA1 or other genes	7, 9

Table 2: HDGC Types and Related Syndromes

Classic HDGC

Classic HDGC is defined by the presence of diffuse-type gastric adenocarcinoma, often with signet ring cell morphology, in individuals or families carrying pathogenic CDH1 mutations 2 3 6 7. The cancer is characterized by:

• Multifocality: Multiple small cancer foci across the stomach lining.
• Early age of onset: Often diagnosed before age 40.
• Associated cancer types: Includes an increased risk for lobular breast cancer, especially in women 2 4 7.

HDGC-like and HLBC

• HDGC-like: Some families meet the clinical criteria for HDGC (early onset, multiple relatives affected), but no causative mutation is identified. These cases are termed “HDGC-like” and may reflect mutations in genes not yet discovered or environmental modifiers 2 8 9.
• HLBC: The 2020 IGCLC guidelines recognize “hereditary lobular breast cancer” (HLBC) for families with pathogenic CDH1 mutations but only manifesting as lobular breast cancer, not gastric cancer 2 8.

Other Genetic Subtypes

• CDH1-negative HDGC: A minority of HDGC families have pathogenic variants in other genes, most notably CTNNA1. Mutations in BRCA2, STK11, and others are rarer but have been described 7 9.
• Syndromic Associations: Familial gastric cancer can also be seen in hereditary cancer syndromes such as Lynch, Peutz-Jeghers, and Li-Fraumeni, but these are distinct from HDGC 3 9.

Causes of Hereditary Diffuse Gastric Cancer

The root of HDGC lies in inherited mutations that disrupt normal cell adhesion and polarity, leading to uncontrolled cell growth in the gastric lining. Understanding the genetic and molecular mechanisms is crucial for risk assessment and counseling.

Cause	Mechanism	Prevalence in HDGC	Source(s)
CDH1 germline mutations	Loss of E-cadherin, cell adhesion	~40–50%	1, 6, 7, 9, 10
CTNNA1 germline mutations	Disrupts cell–cell adhesion	<5%	7, 9
Promoter hypermethylation (second hit)	Epigenetic silencing of CDH1	Common in lesions	1
Other tumor suppressor genes	Impaired cell regulation	Rare	7, 9
Unknown/undiscovered genes	Not yet clarified	~50–60%	9

Table 3: Genetic and Molecular Causes

Genetic Mutations

• CDH1 Gene: The vast majority of HDGC cases with a known genetic cause result from pathogenic germline mutations in the CDH1 gene, which encodes E-cadherin, a critical protein for cell-to-cell adhesion in epithelial tissues 1 6 7 9 10. Loss of E-cadherin disrupts cell polarity, enabling cells to detach and invade surrounding tissues.
• Other Genes: A small subset of HDGC families harbor mutations in CTNNA1, which also plays a role in cell adhesion. Even more rarely, mutations in genes such as BRCA2, STK11, and others have been linked to familial diffuse gastric cancer 7 9.

Two-Hit Hypothesis

For cancer to develop, both alleles of CDH1 must be inactivated. Typically, individuals inherit one mutated allele (germline mutation) and acquire a “second hit” through somatic changes such as promoter hypermethylation, which silences the remaining functional copy 1.

Other Contributors

• Epigenetics: Epigenetic modifications, especially methylation of the CDH1 promoter, are a common “second hit” mechanism in HDGC pathogenesis 1.
• Unknown Genes: In roughly half of families meeting HDGC clinical criteria, no mutation in CDH1 or other known genes is found, indicating that additional genetic or environmental factors are involved 9.

Hereditary Pattern

HDGC is inherited in an autosomal dominant manner, meaning a single copy of the mutated gene is sufficient to confer high risk. The lifetime risk of developing diffuse gastric cancer for CDH1 mutation carriers is estimated at 70% for men and up to 56–83% for women, with an additional 20–40% risk of lobular breast cancer in women 4 7 9.

Treatment of Hereditary Diffuse Gastric Cancer

Managing HDGC requires a nuanced, proactive approach centered on risk reduction, early detection, and ongoing surveillance. The main challenge is that conventional therapies for sporadic gastric cancer are less effective due to the diffuse, multicentric nature of HDGC.

Treatment Approach	Strategy/Goal	Recommended For	Source(s)
Prophylactic total gastrectomy	Remove all gastric mucosa, eliminate risk	CDH1/CTNNA1 mutation carriers	2, 4, 6, 8, 10, 12
Endoscopic surveillance	Early detection of microscopic lesions	Those postponing surgery	5, 8, 11
Breast cancer surveillance	Annual MRI (women)	Female CDH1/CTNNA1 carriers	2, 6, 8, 11
Genetic counseling	Risk assessment, family testing	At-risk individuals	6, 8
Standard cancer therapy	Chemotherapy, targeted therapy	Advanced/metastatic disease	6, 10

Table 4: HDGC Management Strategies

Prophylactic Total Gastrectomy

• Gold Standard: For individuals with a confirmed pathogenic CDH1 (or rarely CTNNA1) mutation, the definitive and most effective strategy to prevent gastric cancer is prophylactic total gastrectomy—removal of the entire stomach, ideally before cancer develops 2 4 6 8 10 12.
• Timing: Surgery is usually recommended between ages 20–30, or 5 years younger than the youngest case in the family 6.
• Effectiveness & Risks: Pathological examination shows that almost all asymptomatic carriers have early microscopic cancer foci, making the surgery more curative than preventive. However, total gastrectomy carries significant risks: nutritional deficiencies, weight loss, and long-term impacts on quality of life 6 12.

Endoscopic Surveillance

• Indication: For those unwilling or unfit for surgery, or wishing to delay it, annual or biannual endoscopic surveillance with systematic random biopsies is recommended 5 8 11.
• Challenges: Early cancer foci are invisible to standard white-light endoscopy; thus, advanced techniques (chromoendoscopy, narrow band imaging) and random biopsies are essential 5 11.
• Limitations: Surveillance may miss small lesions and is less effective than surgery in risk reduction 5 8.

Breast Cancer Surveillance

• Female Carriers: Women with CDH1/CTNNA1 mutations should undergo annual breast MRI starting at age 30 due to increased risk of lobular breast cancer 2 6 8 11.
• Prophylactic Mastectomy: Not routinely recommended but can be considered on a case-by-case basis 11.

Genetic Counseling and Testing

• Family Screening: All first-degree relatives of mutation carriers should be offered genetic counseling and testing to identify those at risk and guide management 6 8.
• Psychosocial Support: The decision for preventive surgery or ongoing surveillance is complex and should be supported by multidisciplinary teams.

Standard Cancer Treatment

• Advanced Disease: If HDGC is diagnosed at an advanced stage, treatment options align with those for sporadic gastric cancer—chemotherapy, targeted therapies, and palliative care—but outcomes are typically poor due to late diagnosis and diffuse spread 6 10.

Conclusion

Hereditary Diffuse Gastric Cancer is a challenging but increasingly manageable syndrome thanks to advances in genetic testing, surveillance, and preventive care.

Key Points:

• HDGC is caused primarily by inherited mutations in the CDH1 gene, leading to a high risk of diffuse gastric cancer and, in women, lobular breast cancer.
• Symptoms are often absent in early disease; cancer typically presents as multiple microscopic foci of signet ring cell carcinoma.
• Types include classic HDGC, HDGC-like (no known mutation), and hereditary lobular breast cancer.
• Prophylactic total gastrectomy is the gold standard for risk reduction in mutation carriers, with endoscopic surveillance as an alternative for selected individuals.
• Annual breast MRI is recommended for female mutation carriers due to increased breast cancer risk.
• Genetic counseling and family testing are critical for identifying at-risk individuals.
• Ongoing research is needed to uncover additional genetic causes and optimize management.

Empowering high-risk families through genetic knowledge, vigilant screening, and proactive management can transform the outlook for those affected by this devastating, but now more preventable, cancer syndrome.