While most stomach cancer cases arise sporadically from environmental factors and aging, a smaller proportion, approximately 1% to 3%, are hereditary. These cases are linked to specific genetic changes passed down through families. Understanding this hereditary connection, particularly maternal inheritance, can help individuals assess personal risk and explore preventive measures.
Understanding Hereditary Cancer
Cancer is a genetic disease, but not all cancers are inherited. Most are “sporadic,” resulting from random genetic mutations that accumulate in cells over a person’s lifetime due to aging, environmental exposures, or lifestyle choices. These mutations are confined to tumor cells and are not passed on to offspring.
In contrast, “hereditary cancers” arise from germline mutations, genetic alterations present in nearly every cell of the body, including reproductive cells. These mutations are inherited from a parent and can be passed down to future generations. While inheriting such a mutation increases cancer predisposition, it does not guarantee cancer will develop. “Familial cancer” represents a middle ground, where multiple family members are affected but no specific inherited gene mutation is identified; this clustering might be due to shared environmental factors or minor genetic influences.
Genetic Links to Stomach Cancer and Maternal Inheritance
The CDH1 gene is primarily associated with Hereditary Diffuse Gastric Cancer (HDGC), a rare but aggressive form of hereditary stomach cancer. It provides instructions for making E-cadherin, a protein crucial for cell adhesion; a mutation can disrupt normal cell growth. HDGC is inherited in an autosomal dominant pattern, meaning only one copy of the altered CDH1 gene is sufficient to increase cancer risk.
If a mother carries a pathogenic CDH1 variant, each of her children, regardless of gender, has a 50% chance of inheriting that mutated gene. Earlier estimates suggested a lifetime stomach cancer risk up to 70-80% for CDH1 mutation carriers, but recent studies indicate a range of 10-38%, with higher risks in families with a strong history of invasive gastric cancer. Women with a CDH1 mutation also face an elevated risk of lobular breast cancer, estimated between 37% and 55%.
Other genetic syndromes can also increase stomach cancer risk. Lynch syndrome, caused by mutations in mismatch repair genes (MLH1, MSH2, MSH6, PMS2, EPCAM), primarily raises the risk of colorectal and endometrial cancers but also increases stomach cancer risk, with a lifetime risk up to 13% in Western countries. Familial Adenomatous Polyposis (FAP), linked to mutations in the APC gene, significantly increases colorectal cancer risk and can also lead to stomach polyps, with a low but present risk of gastric cancer. Li-Fraumeni syndrome, caused by TP53 gene mutations, is associated with a broad spectrum of cancers, including a younger age of gastric cancer onset.
Assessing Your Risk and Genetic Counseling
Understanding your family medical history is an important initial step in assessing personal risk for hereditary stomach cancer. Gathering detailed information about relatives who have had cancer, including the type, age at diagnosis, and their relationship to you, provides valuable insights. A strong family history might include multiple family members with stomach cancer, early-onset stomach cancer (before age 50), or specific types like diffuse gastric cancer.
Genetic counseling is important in this assessment process. A genetic counselor can review your family history, help determine if you meet criteria for genetic testing, and explain the implications of genetic test results. Individuals with multiple cases of stomach cancer in their family, particularly at younger ages, or those with a known genetic mutation, should consider genetic counseling. The counseling process involves a comprehensive risk assessment, education about inheritance patterns and associated cancers, discussion of testing options, and psychosocial support to navigate complex decisions.
Management and Prevention Strategies
For individuals identified as high-risk due to a confirmed hereditary predisposition, such as a CDH1 gene mutation, specific medical management and prevention strategies are recommended. Due to the diffuse nature of HDGC, which makes early detection challenging through standard endoscopy, increased surveillance is often insufficient. Prophylactic total gastrectomy, the surgical removal of the entire stomach, is considered the most effective preventive measure for CDH1 mutation carriers, significantly reducing stomach cancer risk. This procedure is typically recommended early in adulthood, often between ages 20 and 30.
After a prophylactic gastrectomy, individuals require lifelong nutritional management and regular monitoring for potential complications. While this is a significant and life-altering surgery, it eliminates the primary site of HDGC risk. For other hereditary syndromes, surveillance strategies vary, but often involve regular endoscopies with biopsies to detect precancerous changes or early-stage cancer. While lifestyle factors like diet and smoking influence overall cancer risk, for hereditary forms, genetic predisposition is the primary determinant, necessitating more aggressive preventive approaches.