MLH1

The MLH1 gene plays a crucial role in DNA mismatch repair, encoding the MLH1 protein that forms essential complexes like MutLα with PMS2 to correct replication errors and maintain genomic stability. 

This gene's mutations are associated with Lynch syndrome, increasing risks for colorectal, endometrial, and other cancers.  

Additionally, MLH1 defects contribute to Turcot syndrome, marked by brain tumors and colorectal polyps. 

Understanding the diverse functions and implications of MLH1 mutations is vital for advancing targeted treatments and genetic testing strategies to manage and prevent associated syndromes and cancers.

Understanding MLH1  [1., 2., 8., 9.] 

MLH1 is integral to the cellular machinery responsible for DNA repair; specifically, MLH1 is part of a system of seven DNA mismatch repair proteins working sequentially within the mismatch repair (MMR) system. 

The MLH1 gene provides instructions for making the MLH1 protein that plays an essential role in repairing DNA.  

The MLH1 protein joins with another protein called PMS2 to form a complex called MutLα, which coordinates the activities of other proteins that repair errors made during DNA replication.  

The repairs are made by removing a section of DNA that contains errors and replacing it with a corrected DNA sequence.

MLH1 is also involved in DNA damage signaling and can form a complex called MutLγ with MLH3, which is involved in meiosis.

Germline mutations in the MLH1 gene are known to cause Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC).  The most common malignancies in Lynch syndrome are colorectal and endometrial carcinomas, although ovarian cancer can also occur.  [11.] 

Variants in the MLH1 gene can also cause Turcot syndrome, a rare disorder characterized by the development of brain tumors and colorectal polyps.  Defects in MLH1 are associated with the microsatellite instability observed in hereditary nonpolyposis colon cancer.

In summary, the MLH1 gene encodes a protein that is essential for DNA mismatch repair and plays a crucial role in maintaining genomic stability. Alterations in the MLH1 gene can lead to Lynch syndrome, Turcot syndrome, and various types of cancer, particularly colorectal and endometrial carcinomas.

Diseases Associated with MLH1 Gene Mutations

Lynch Syndrome  [2., 4., 11., 12.] 

Lynch syndrome (LS) is a dominantly inherited cancer susceptibility syndrome defined by the presence of pathogenic variants in DNA mismatch repair genes including MLH1, MSH2, MSH6, and PMS2.

It is estimated to affect about 1 in 400 people in the UK, but only 5% of those with the condition are aware of the diagnosis.  [2.] 

LS results in a high lifetime risk of colorectal, endometrial, gastric, ovarian, hepatobiliary, brain, and other cancers.  Interventions such as high-quality 2-yearly colonoscopy, prophylactic gynecological surgery, and aspirin are proven to prevent and facilitate early diagnosis of cancers in this population, improving patient outcomes.

Gastroenterologists and other non-genetics service clinicians may now offer 'mainstreamed' genetic testing for LS to patients with cancer.  [2., 4.]   

Patients diagnosed with LS require lifelong coordinated multidisciplinary care, where the application of gene-specific interventions provides many opportunities to reduce cancer risk.

LS is a highly variable entity, with some patients presenting at very young ages with malignancy, while others may never develop cancer despite carrying an unequivocal genetic predisposition.  Environmental factors such as smoking and excessive alcohol consumption can influence disease expression on a background of significant genetic risk.

Turcot Syndrome  [5., 10.]

Turcot syndrome (TS) is a rare genetic disorder characterized by the association of primary brain tumors with colorectal cancer or colorectal polyposis.  There are two main types of Turcot syndrome:

• Turcot syndrome type 1 (TS1): associated with mutations in DNA mismatch repair (MMR) genes, such as MLH1, MSH2, MSH6, and PMS2. It is often associated with hereditary non-polyposis colorectal cancer (HNPCC) or Lynch syndrome

• Turcot syndrome type 2 (TS2): associated with mutations in the APC gene, which is also linked to familial adenomatous polyposis (FAP)

The most common characteristics of Turcot syndrome are intestinal polyps and brain or spinal cord tumors.  Intestinal polyps may cause rectal bleeding, diarrhea, and abdominal pain, while brain tumors can lead to neurological symptoms such as headaches, blurred vision, and balance issues.

Turcot syndrome is an extremely rare condition, with only around 150 cases reported in medical journals.

Increased Risk of Certain Cancers

As noted above, germline mutations in the MLH1 gene are known to cause Lynch syndrome, which is associated with an increased risk of various cancers.  The most common malignancies in Lynch syndrome are colorectal and endometrial carcinomas.  

Individuals with an MLH1 pathogenic variant have a lifetime colorectal cancer risk of 46-61% and an endometrial cancer risk of 34-54%.  [6.]

Other cancers linked to MLH1 variations include gastric cancer (5-7% lifetime risk), ovarian cancer (4-20% lifetime risk), and biliary tract cancer (1.9-3.7% lifetime risk).  [6.] 

In rare cases, MLH1 mutations can also lead to constitutional mismatch repair deficiency (CMMRD) syndrome, which is associated with an increased risk of childhood cancers such as brain tumors, leukemia, and lymphoma.  [7.]

Genetic Alterations in the MLH1 Gene

The gene for the MLH1 protein may contain alterations or mutations that cause alterations of function of the MLH1 protein.  

Testing for genetic alterations in the form of SNPs is increasingly available and can shed light on an individual’s potential for health and disease.  

What is a SNP?

A SNP, or single nucleotide polymorphism, refers to a variation at a single position in a gene along its DNA sequence.  A gene encodes a protein, so an alteration in that gene programs the production of an altered protein.  

As a type of protein with great functionality in human health, alterations in genes for enzymes may confer a difference in function of that enzyme.  The function of that enzyme may be increased or decreased, depending on the altered protein produced.  

SNPs are the most common type of genetic variation in humans and can occur throughout the genome, influencing traits, susceptibility to diseases, and response to medications.

The completion of the Human Genome Project has significantly expanded opportunities for genetic testing by providing a comprehensive map of the human genome that facilitates the identification of genetic variations associated with various health conditions, including identifying SNPs that may cause alterations in protein structure and function.  

Genetic testing for SNPs enables the identification of alterations in genes, shedding light on their implications in health and disease susceptibility.

Laboratory Testing for MLH1

Genetic testing for single nucleotide polymorphisms (SNPs) typically involves obtaining a sample of DNA which can be extracted from blood, saliva, or cheek swabs. 

The sample may be taken in a lab, in the case of a blood sample.  Alternatively, a saliva or cheek swab sample may be taken from the comfort of home. 

Test Preparation

Prior to undergoing genetic testing, it's important to consult with a healthcare provider or genetic counselor to understand the purpose, potential outcomes, and implications of the test.  This consultation may involve discussing medical history, family history, and any specific concerns or questions. 

Additionally, individuals may be advised to refrain from eating, drinking, or chewing gum for a short period before providing a sample to ensure the accuracy of the test results.  Following sample collection, the DNA is processed in a laboratory where it undergoes analysis to identify specific genetic variations or SNPs. 

Once the testing is complete, individuals will typically receive their results along with interpretation and recommendations from a healthcare professional. 

It's crucial to approach genetic testing with proper understanding and consideration of its implications for one's health and well-being.

Patient-Centric Approaches

A patient-centered approach to SNP genetic testing emphasizes individualized medicine, tailoring healthcare decisions and interventions based on an individual's unique genetic makeup.

When that is combined with the individual’s health status and health history, preferences, and values, a truly individualized plan for care is possible. 

By integrating SNP testing into clinical practice, healthcare providers can offer personalized risk assessment, disease prevention strategies, and treatment plans that optimize patient outcomes and well-being. 

Genetic testing empowers a deeper understanding of genetic factors contributing to disease susceptibility, drug response variability, and overall health, empowering patients to actively participate in their care decisions. 

Furthermore, individualized medicine recognizes the importance of considering socioeconomic, cultural, and environmental factors alongside genetic information to deliver holistic and culturally sensitive care that aligns with patients' goals and preferences. 

Through collaborative decision-making and shared decision-making processes, patients and providers can make informed choices about SNP testing, treatment options, and lifestyle modifications, promoting patient autonomy, engagement, and satisfaction in their healthcare journey.

Genetic Panels and Combinations

Integrating multiple biomarkers into panels or combinations enhances the predictive power and clinical utility of pharmacogenomic testing.  

Biomarker panels comprising a variety of transporter proteins and enzymes including drug metabolizing enzymes offer comprehensive insights into individual drug response variability and treatment outcomes. 

Combining genetic SNP testing associated with drug transport, metabolism, and pharmacodynamics enables personalized medicine approaches tailored to individual patient characteristics and genetic profiles.

Order Genetic Testing

Click here to compare genetic test panels and order genetic testing for health-related SNPs.