DNA strand intertwined with a stomach, symbolizing genetic links to gastric cancer.

Decoding Hereditary Gastric Cancer: What You Need to Know About CDH1 Mutations

Theo Raines in Health & Wellness August 2025 • 4 min read.

"Unraveling the Mystery of Diffuse Gastric Cancer: How Genetic Insights Can Save Lives"

Gastric cancer, a formidable adversary, ranks as a leading cause of cancer-related deaths worldwide. While various factors contribute to its development, a significant concern arises when gastric cancer appears to run in families. Hereditary Diffuse Gastric Cancer (HDGC) is a particularly insidious form of this disease, often linked to genetic mutations that can be passed down through generations.

At the heart of HDGC lies a gene called CDH1, which provides the blueprint for E-cadherin, a vital protein responsible for cell adhesion. When CDH1 harbors mutations, E-cadherin's function is compromised, leading to the development of diffuse gastric cancer. Understanding the intricacies of CDH1 mutations is paramount for early detection, risk assessment, and proactive management of this hereditary cancer.

Recent research has shed light on the complexities of HDGC, particularly in cases where the common culprit, Helicobacter pylori (H. pylori) infection, is absent. A groundbreaking study delved into a Japanese family affected by HDGC, revealing that CDH1 mutations can be the primary driver of cancer development even without H. pylori involvement. This article explores the key findings of this study, offering insights into the genetic landscape of HDGC and its implications for individuals and families at risk.

Unmasking the Genetic Culprit: The CDH1 Mutation Connection

DNA strand intertwined with a stomach, symbolizing genetic links to gastric cancer.

The study focused on a Japanese family where two siblings were diagnosed with gastric cancer at a young age. The brother, unfortunately, succumbed to advanced gastric cancer at 28, while his sister was diagnosed with intramucosal signet ring cell carcinoma (SRCC) at 27. Genetic testing revealed that both siblings carried an identical germline CDH1 mutation, meaning the mutation was inherited from their parents.

Interestingly, the brother tested positive for H. pylori infection, a known risk factor for gastric cancer, while the sister was H. pylori-negative. This observation raised a critical question: Could CDH1 mutations alone drive cancer development in the absence of H. pylori? To investigate further, the researchers conducted whole-exome sequencing (WES) on the sister's intramucosal SRCC.

WES unveiled seven somatic mutations in the sister's cancer cells, including one in CDH1.
Further analysis indicated that the six non-CDH1 mutations were likely non-driver mutations, meaning they did not actively contribute to cancer development.
Immunohistochemistry confirmed decreased expression of E-cadherin in the SRCC tissue, highlighting the impact of CDH1 mutations on protein function.

These findings strongly suggest that CDH1 mutation was the sole active driver mutation in this case of H. pylori-uninfected intramucosal SRCC. This discovery has significant implications for individuals with a family history of gastric cancer, particularly those who test negative for H. pylori.

Empowering Prevention and Early Detection: What You Can Do

If you have a family history of gastric cancer, especially if it includes multiple cases or early-onset diagnoses, it's crucial to consider genetic counseling and testing for CDH1 mutations. Early detection and preventive measures can significantly improve outcomes. While gastric cancer remains a significant health challenge, advancements in genetic research offer hope for more effective prevention and treatment strategies. Understanding your risk and taking proactive steps can make all the difference.

About this Article -

This article was crafted using a human-AI hybrid and collaborative approach. AI assisted our team with initial drafting, research insights, identifying key questions, and image generation. Our human editors guided topic selection, defined the angle, structured the content, ensured factual accuracy and relevance, refined the tone, and conducted thorough editing to deliver helpful, high-quality information.See our About page for more information.

This article is based on research published under:

DOI-LINK: 10.1007/s10120-018-00912-w, Alternate LINK

Title: Genetic Analysis Of A Case Of Helicobacter Pylori-Uninfected Intramucosal Gastric Cancer In A Family With Hereditary Diffuse Gastric Cancer

Subject: Cancer Research

Journal: Gastric Cancer

Publisher: Springer Science and Business Media LLC

Authors: Taro Funakoshi, Shin’Ichi Miyamoto, Nobuyuki Kakiuchi, Mitsuhiro Nikaido, Takeshi Setoyama, Akira Yokoyama, Takahiro Horimatsu, Atsushi Yamada, Masako Torishima, Shinji Kosugi, Hidetaka Yamada, Haruhiko Sugimura, Hironori Haga, Yoshiharu Sakai, Seishi Ogawa, Hiroshi Seno, Manabu Muto, Tsutomu Chiba

Published: 2018-12-12

Everything You Need To Know

What exactly is Hereditary Diffuse Gastric Cancer (HDGC), and why is it a concern?

Hereditary Diffuse Gastric Cancer (HDGC) is a specific type of gastric cancer that tends to run in families. It's often associated with genetic mutations passed down through generations. The insidious nature of HDGC stems from its diffuse pattern of growth within the stomach lining, making it challenging to detect early. Understanding HDGC is crucial for individuals with a family history of gastric cancer, as it allows for proactive measures like genetic testing and early screening.

How do CDH1 gene mutations impact cell function, and what's the role of E-cadherin?

The CDH1 gene provides the instructions for making E-cadherin, a protein vital for cell adhesion. E-cadherin helps cells stick together, forming a barrier and preventing uncontrolled growth. When the CDH1 gene has mutations, the resulting E-cadherin protein doesn't function correctly. This loss of cell adhesion can lead to the development of diffuse gastric cancer, where cancer cells spread more easily within the stomach lining. The compromised function of E-cadherin due to CDH1 mutations is a key factor in the progression of HDGC.

What significant finding came from the research on the Japanese family regarding CDH1 mutations and H. pylori?

The study on the Japanese family revealed that CDH1 mutations can be the primary driver of cancer development even in the absence of Helicobacter pylori (H. pylori) infection. In the study, a sister who was H. pylori-negative, was found to have CDH1 mutations that solely drove cancer development. Whole-exome sequencing (WES) helped identify this CDH1 mutation. This finding challenges the traditional understanding of gastric cancer development, which often emphasizes H. pylori as a major risk factor. It highlights the importance of considering genetic factors, especially CDH1 mutations, in individuals with a family history of gastric cancer, regardless of their H. pylori status.

How does genetic testing for CDH1 mutations work, and who should consider getting tested?

Genetic testing for CDH1 mutations involves analyzing an individual's DNA, usually from a blood sample, to identify any alterations in the CDH1 gene sequence. This testing is particularly recommended for individuals with a family history suggestive of HDGC, such as multiple cases of gastric cancer, early-onset diagnoses (before age 50), or a family history of lobular breast cancer. Genetic counseling can help individuals understand the implications of genetic testing, including the potential risks and benefits, as well as guide them in making informed decisions about their healthcare. If a CDH1 mutation is identified, increased surveillance and prophylactic gastrectomy could be considered.

Besides CDH1 mutations, what other factors contribute to the development of gastric cancer?

While the study focused on CDH1 mutations and their role in HDGC, it's important to remember that gastric cancer is a complex disease influenced by multiple factors. Other genes, such as CTNNA1, also contribute to hereditary gastric cancer, although CDH1 is the most frequently mutated gene. Additionally, lifestyle factors like diet and smoking, as well as environmental exposures, can also play a role in gastric cancer development. A comprehensive approach to risk assessment and prevention should consider both genetic and non-genetic factors.