What is the penetrance of Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer)?

From the Guidelines

Lynch syndrome has incomplete penetrance, with an estimated penetrance of 30-74% for colorectal cancer, depending on the specific mismatch repair gene mutated, as reported in the 2014 guidelines on genetic evaluation and management of Lynch syndrome 1. The penetrance of Lynch syndrome varies depending on the specific gene mutation, with MLH1 and MSH2 mutations having a higher risk of colorectal cancer, ranging from 30% to 74%, while MSH6 and PMS2 mutations have a lower cumulative lifetime risk, ranging from 10% to 22% and 15%-20%, respectively 1. Some key points to consider when evaluating the penetrance of Lynch syndrome include:

• The type of gene mutation, with MLH1 and MSH2 mutations having a higher risk of colorectal cancer
• The age of diagnosis, with a mean age of 46-61 years for colorectal cancer in Lynch syndrome patients
• The location of the tumor, with 60%-80% of colorectal tumors arising on the right side of the colon
• The risk of metachronous colorectal cancer, with a high rate of 16% at 10 years and 41% at 20 years after segmental surgical resection of the initial colorectal cancer
• The risk of extracolonic malignancies, including endometrial cancer, which occurs in up to 54% of women with MLH1 and MSH2 mutations. It is essential to consider these factors when providing genetic counseling to individuals with Lynch syndrome mutations, as they may never develop cancer despite carrying the mutation, and regular surveillance screenings are crucial for early detection and prevention of Lynch syndrome-associated cancers 1.

From the Research

Penetrance of Lynch Syndrome

The penetrance of Lynch syndrome, also known as Hereditary Nonpolyposis Colorectal Cancer, varies depending on the gender and the specific mismatch repair gene mutation.

• The cumulative risk of colorectal cancer (CRC) is estimated to be around 66.08% for men and 42.71% for women, with an overall hazard ratio of 148.4 and 51.1, respectively 2.
• The cumulative risk of endometrial cancer is estimated to be around 39.39% for women, with an overall hazard ratio of 39.0 2.
• The lifetime risk of CRC is estimated to be between 50-70% and the lifetime risk of endometrial cancer is estimated to be between 40-60% 3, 4.
• The risk of CRC and endometrial cancer in Lynch syndrome is high, with some studies suggesting that the risk of endometrial cancer equals or exceeds the risk of CRC in women with Lynch syndrome 3, 5.

Factors Influencing Penetrance

The penetrance of Lynch syndrome can be influenced by various factors, including:

• The specific mismatch repair gene mutation, with some mutations conferring a higher risk of certain cancers 2.
• Gender, with men having a higher cumulative risk of CRC than women 2.
• Age, with the risk of cancer increasing with age 2, 3.

Clinical Implications

The high penetrance of Lynch syndrome has important clinical implications, including:

• The need for specialized cancer surveillance and risk-reduction strategies, such as colectomy and prophylactic hysterectomy and bilateral oophorectomy 3, 5.
• The importance of genetic counseling and germline testing for individuals with a family history of Lynch syndrome 4.