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The Mystery of Genes: Why Mutations in MLH1 and MSH2 Put You at Higher Risk of Cancer?
In the study of hereditary cancers, Muir–Torre syndrome has attracted widespread attention from the medical community. This is a rare auto-dominant cancer syndrome commonly considered a subtype of hereditary nonpolyposis colon cancer (HNPCC) in which mutations occur primarily in the MLH1 and MSH2 genes.
These genes are closely related to the DNA mismatch repair process, and their mutations significantly increase the risk of cancer.
Patients with Muir-Torre syndrome often develop colon cancer, urogenital cancer, and skin lesions such as keratocysts and sebaceous gland tumors. The diagnostic criteria for this syndrome are usually based on the Amsterdam criteria, which mainly include:
- Have at least three relatives with HNPCC-related cancer
- At least two generations have been affected by cancer
- Have at least one first-degree relative with cancer, and at least one was diagnosed with colon cancer before age 50.
In addition to genetic mutations, the diagnosis of this syndrome depends on the patient's family history and histological verification of the tumor. Studies have found that although many patients with MSH2 and MLH1 gene mutations have cutaneous sebaceous gland tumors, they do not necessarily meet the diagnostic criteria for Muir–Torre syndrome.
In current research and clinical practice, the Mayo Muir-Torre syndrome risk score system is used to improve the positive predictive value of this syndrome.
The Mayo Muir-Torre risk scoring system scoring criteria are as follows:
- Age of first onset <60 years old scores 1 point; >60 years old scores 0 points
- Number of skin tumors: 1, 0 points; > 2, 2 points
- Personal history of cancer: 0 points for no, 1 point for yes
- Whether there is a family history of cancer: 0 points for no, 1 point for yes
According to this scoring system, those with a score of 2 and above have a higher positive predictive value, while those with a score of 1 and below are less likely to have Muir–Torre syndrome.
Based on current research, the most common internal malignancies associated with Muir–Torre syndrome include colon (56%), genitourinary (22%), small bowel (4%), and breast (4%) ). However, this syndrome may also be associated with other types of internal malignancies and should be a cause for concern.
Genetic causes
The genetic cause of Muir–Torre syndrome is mainly related to mutations in the MLH1 and MSH2 genes. These genes are responsible for mismatch repair in the DNA repair process. Mutations can seriously damage the function of the genes and increase the risk of cancer.
Multiple studies have shown some genetic overlap between Muir–Torre syndrome and Turcot syndrome.
In addition, a study showed that a patient with MSH2 and MSH6 gene defects suffered from both syndromes, which is the first confirmed case of the merger. In addition to skin tumors, the patient also developed brain tumors, which are characteristic of Turcot syndrome. The discovery provides new insights into the genetic basis of these diseases.
Diagnosis and Treatment
In the past, clinical diagnosis of Muir–Torre syndrome mainly relied on pathological examination. With the development of immunohistochemistry technology, this method is increasingly used to evaluate genetic defects in patients and identify the possibility of inherited DNA mismatch repair defects.
Repeated immunohistochemistry testing helps clinicians identify potential Muir–Torre syndrome patients at an early stage.
Current treatments typically include oral isotretinoin, a drug that effectively prevents tumor development. In addition to medication, people with Muir–Torre syndrome undergo the same rigorous cancer screening as Lynch syndrome, including early and frequent colonoscopies, mammograms, skin exams, and imaging of the abdomen and pelvis.
Epidemiology
Research shows that Muir–Torre syndrome occurs in 9.2% of people with Lynch syndrome. Of these, approximately 70% of tumors associated with this syndrome have microsatellite instability. The MLH1 and MSH2 gene defects associated with HNPCC are prevalent in patients with Muir-Torre syndrome, and the proportion of patients with MSH2 mutations is as high as 90%.
Consequently, cancers of the digestive and urinary systems are the most common internal malignancies, with colon cancer being the most common.
Conclusion
The syndrome is named after two pioneers in the medical field, Edward Grainger Muir and Douglas P. Torre. In the 1960s, Muir came to the attention of the medical community when he diagnosed a patient with multiple keratocysts who subsequently developed multiple internal malignancies. However, as the syndrome is further studied, can we truly unravel the mystery of the genetic link between Muir–Torre syndrome and other cancers?
