What is the inheritance pattern for Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer)?

From the Guidelines

Lynch syndrome follows an autosomal dominant inheritance pattern, meaning that a person only needs to inherit one defective copy of a mismatch repair gene from either parent to develop the condition. This pattern is characterized by a high risk of colorectal cancer, endometrial cancer, and other malignancies, with a lifetime risk of up to 80% for colorectal cancer 1. The syndrome is caused by germline mutations in DNA mismatch repair genes, primarily MLH1, MSH2, MSH6, and PMS2, with occasional mutations in EPCAM, leading to microsatellite instability and accumulation of DNA replication errors 1.

Key Features of Lynch Syndrome

• Autosomal dominant inheritance pattern
• High risk of colorectal cancer, endometrial cancer, and other malignancies
• Caused by germline mutations in DNA mismatch repair genes
• Microsatellite instability and accumulation of DNA replication errors
• Variable expressivity, with specific cancer types and age of onset varying within families

Implications for Diagnosis and Management

• Genetic testing is essential for diagnosis
• Affected individuals require intensive cancer surveillance beginning at an earlier age than the general population
• Surveillance offers an opportunity for early detection and perhaps even prevention of cancer among mutation carriers
• Cancer site-specific evaluation and heightened attention to symptoms is also advised for other cancers that occur with increased frequency in affected persons 1.

Inheritance Pattern and Risk

Each child of an affected individual has a 50% chance of inheriting the mutation, highlighting the importance of genetic testing and counseling for families with a history of Lynch syndrome 1. The condition demonstrates high penetrance but variable expressivity, meaning that individuals with the mutation have a high likelihood of developing cancer, but the specific cancer types and age of onset can vary considerably even within families 1.

From the Research

Inheritance Pattern of Lynch Syndrome

The inheritance pattern of Lynch syndrome is characterized as:

• Autosomal dominant genetic disorder 2, 3, 4
• Caused by germline mutations in DNA mismatch repair (MMR) genes 2, 3, 4
• Carriers of pathogenic mutations in these genes have an increased risk of developing colorectal cancer and/or Lynch syndrome-associated cancer 2, 3, 4

Cancer Risks Associated with Lynch Syndrome

Individuals with Lynch syndrome are at risk of developing various types of cancer, including:

• Colorectal cancer 2, 3, 4
• Endometrial cancer 2, 3, 4
• Ovarian cancer 2, 3, 5, 6
• Other cancers, such as stomach, small intestine, and brain cancer 2

Management and Prevention Strategies

To manage and prevent Lynch syndrome-associated cancers, the following strategies are recommended:

• Genetic testing to identify carriers of pathogenic mutations in MMR genes 2, 3
• Regular surveillance, including colonoscopy and endometrial sampling 3, 5
• Prophylactic surgeries, such as hysterectomy and bilateral salpingo-oophorectomy, may be considered for women with Lynch syndrome 5, 6