Lynch syndrome is a hereditary condition that significantly increases the lifetime risk for several cancers, particularly colorectal and endometrial cancers. It is caused by an inherited alteration in one of the mismatch repair (MMR) genes, including MLH1, MSH2, MSH6, and PMS2. A pathogenic variant in the MSH6 gene defines a distinct subtype, often called MSH6-associated Lynch syndrome. This inherited change means every cell carries one non-working copy of the MSH6 gene, increasing cancer susceptibility. Understanding the function of the MSH6 gene and the resulting cancer risks is crucial for effective prevention and early detection.
The Role of MSH6 in DNA Mismatch Repair
The MSH6 gene provides the blueprint for a protein that is a component of the DNA Mismatch Repair (MMR) system. This system acts as a proofreader, correcting errors that occur during DNA replication. The MSH6 protein partners with MSH2 to form the MutS \(\alpha\) complex.
The MutS \(\alpha\) complex recognizes and binds to single-base mismatches or small insertions and deletions in the newly synthesized DNA strand. Once an error is identified, the complex recruits other proteins to excise the faulty section and replace it with the correct sequence. Inheriting a non-functional copy of MSH6 compromises the cell’s ability to perform this repair.
For the repair system to completely shut down, the second, normal copy of the MSH6 gene must also fail or acquire a mutation. This failure leads to the rapid accumulation of errors, causing microsatellite instability (MSI). This high rate of mutation creates the genomic instability necessary to transform a normal cell into a cancerous one.
Specific Cancer Risks Associated with MSH6 Mutations
The cancer risk pattern for individuals with an MSH6 mutation differs from those with MLH1 or MSH2 mutations. MSH6 carriers show a lower lifetime risk for colorectal cancer (CRC) but a higher relative risk for endometrial cancer. For women, the lifetime risk of developing endometrial cancer can be as high as 40%, often presenting around age 55.
CRC is the second most common malignancy associated with MSH6. The lifetime risk is estimated to be around 20% for women and 10% for men. The average age of CRC onset in MSH6 carriers, often in the mid-50s, is later than in carriers of other Lynch syndrome genes, informing personalized surveillance strategies.
Other cancers are also associated with MSH6-related Lynch syndrome. The lifetime risk for ovarian cancer is approximately 10% for women. Both men and women have an increased risk for urothelial cancer (affecting the urinary tract), with a lifetime risk estimated at about 7%. There is also an increased chance of developing stomach, small bowel, and brain cancers.
Genetic Inheritance and Diagnostic Testing
Lynch syndrome caused by an MSH6 mutation follows an autosomal dominant inheritance pattern. This means a person only needs to inherit one copy of the altered gene from one parent to have the condition. An individual with an MSH6 mutation has a 50% chance of passing the mutation on to each child.
The diagnostic process begins with tumor screening in individuals who have developed an associated cancer, such as colorectal or endometrial cancer. This screening typically involves immunohistochemistry (IHC) testing, which looks for the presence or absence of the MSH6 protein in the tumor tissue. Loss of MSH6 protein expression is a strong indicator of an underlying MSH6 germline mutation.
Tumor tissue may also be tested for microsatellite instability (MSI), confirming the MMR system is not working. However, MSH6-related tumors are sometimes classified as microsatellite stable, meaning the instability is less pronounced than in other Lynch syndrome types. If tumor screening suggests Lynch syndrome, a definitive diagnosis is made through germline genetic testing of a blood or saliva sample.
Recommended Surveillance and Management Protocols
Individuals with a confirmed MSH6 mutation require proactive and specialized surveillance protocols to detect cancers at their earliest, most treatable stages. Colorectal cancer screening is advised to begin at a younger age than for the general population. High-quality colonoscopy is recommended every one to three years, typically starting between ages 30 and 35, or five years younger than the earliest family diagnosis if that occurred before age 30.
For women, gynecological surveillance focuses on the high risk for endometrial and ovarian cancers. While screening methods for endometrial cancer are not proven to reduce mortality, some guidelines suggest discussing annual endometrial sampling or transvaginal ultrasound starting between ages 30 and 35. A risk-reducing hysterectomy and removal of the ovaries and fallopian tubes is an option women may consider after childbearing is complete, as this surgery eliminates the risk of both cancers.
Chemoprevention with daily aspirin has been shown to reduce the risk of colorectal and other Lynch syndrome-related cancers. Patients should discuss the benefits and risks of aspirin with their healthcare provider to determine the appropriate dose and timing. Surveillance for other cancers, such as gastric cancer, may involve an upper endoscopy every few years, especially if there is a family history.