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Lynch syndrome (MLH1)
Lynch syndrome is a genetic condition primarily raising the risk of colorectal and endometrial cancers, but also others. It is caused by inherited changes in genes like MLH1, affecting DNA repair, and can impact individuals across generations within a family.
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Overview
Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC), is one of the most common inherited causes of cancer [PMID:28767228]. It significantly increases an individual's lifetime risk of developing certain cancers, particularly colorectal cancer and endometrial cancer, at younger ages than typically seen in the general population. Other cancers, such as those of the stomach, ovary, small bowel, urinary tract, hepatobiliary tract, brain, and skin (sebaceous adenomas/carcinomas and keratoacanthomas), are also associated with Lynch syndrome [PMID:32594611].
This condition is caused by inherited changes (pathogenic variants) in specific genes that play a crucial role in DNA repair. When these genes do not function correctly, errors in DNA can accumulate, leading to uncontrolled cell growth and cancer formation. Understanding Lynch syndrome is important for individuals and families, as it allows for early detection and preventative strategies to reduce cancer risk.
Approximately 1 in 440 people in the general population are estimated to carry a pathogenic variant associated with Lynch syndrome, making it a relatively common inherited cancer predisposition syndrome.
Symptoms & clinical features
Individuals with Lynch syndrome do not typically have noticeable symptoms until cancer develops. The signs and symptoms then depend on the type and location of the cancer. For example, colorectal cancer might present with changes in bowel habits, rectal bleeding, abdominal pain, or unexplained weight loss. Endometrial cancer may lead to abnormal vaginal bleeding.
While Lynch syndrome itself doesn't have 'symptoms' in the traditional sense, a key indicator is a strong family history of the associated cancers. This often includes multiple family members on the same side of the family developing these cancers, especially at younger ages (e.g., under 50 years old), or individuals developing multiple Lynch-associated cancers themselves. If these patterns are observed, it often prompts further investigation and genetic testing for Lynch syndrome.
Some individuals with Lynch syndrome may develop specific non-cancerous growths on the skin, such as sebaceous adenomas or keratoacanthomas, which are benign skin tumours, although these are less common and not always present. The presence of these, particularly in combination with a personal or family history of Lynch-associated cancers, can be a clue.
Video: Is cancer in your genes?
Affected organs
Lynch syndrome primarily affects organs where cells divide rapidly, as this increases the chance of DNA replication errors that the faulty repair mechanism cannot fix. The most frequently affected organs are the colon (large bowel) and the endometrium (lining of the uterus).
Other organs commonly affected include the stomach, small bowel, ovaries, urinary tract (especially the renal pelvis and ureters), and the hepatobiliary tract (liver and bile ducts). Less commonly, the brain and skin can also be affected. The spectrum of cancers and the specific organs involved can vary between individuals with Lynch syndrome, even within the same family.
Risks & severity
The severity of Lynch syndrome lies in the significantly increased lifetime risk of developing various cancers compared to the general population. For individuals with pathogenic MLH1 variants, the lifetime risk of colorectal cancer is estimated to be between 40% and 60%, and for endometrial cancer, it can range from 30% to 60% [PMID:32594611]. These cancers also tend to develop at an earlier age, often before 50 years old, which is a hallmark of the syndrome.
The risks for other associated cancers also increase, though typically to a lesser extent. For instance, the lifetime risk for ovarian cancer is around 7-10%, and for stomach cancer, it's about 1-5%. The exact risks can vary depending on the specific gene involved, the specific variant, and family history. The onset of cancer can vary widely; some individuals may develop multiple cancers, while others may develop none, despite carrying a pathogenic variant. This variability highlights the importance of personalised surveillance and risk management strategies.
Genetic causes
Lynch syndrome is caused by inherited pathogenic variants in genes involved in the mismatch repair (MMR) pathway. These genes include MLH1, MSH2, MSH6, and PMS2. Our focus here is on pathogenic variants in the MLH1 gene.
The MLH1 gene provides instructions for making a protein that is a crucial component of the DNA mismatch repair system. This system acts like a cellular proofreader, identifying and correcting small errors that can occur when DNA is copied (replicated) during cell division. These errors, if left uncorrected, can lead to changes in the DNA sequence (mutations) that may contribute to cancer development.
When a pathogenic variant occurs in MLH1, the protein it produces may be faulty or absent. This impairs the cell's ability to efficiently repair DNA mismatches, leading to an accumulation of errors. Over time, these accumulated errors can affect other genes involved in cell growth control, increasing the likelihood of uncontrolled cell division and cancer formation. Therefore, individuals with an MLH1 pathogenic variant have a higher probability of developing Lynch-associated cancers.
- MLH1 mutL homolog 1The *MLH1* gene provides instructions for a protein essential in DNA mismatch repair, a crucial process that corrects errors occurring during DNA replication to maintain genomic integrity.
Inheritance pattern
Lynch syndrome is inherited in an autosomal dominant pattern. This means that an individual only needs to inherit one copy of an altered (pathogenic) gene from one parent to be affected by the condition. The gene is located on a non-sex chromosome (autosome), and the condition affects males and females equally.
If one parent has a pathogenic variant for Lynch syndrome, each child has a 50% chance (1 in 2) of inheriting that variant. Those who inherit the variant are then at an increased risk of developing Lynch-associated cancers during their lifetime. It is important to remember that inheriting the variant means an increased risk, but not a certainty, of developing cancer. Family members who do not inherit the pathogenic variant do not have an increased risk of Lynch syndrome-related cancers above that of the general population and cannot pass the condition on to their children.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
A diagnosis of Lynch syndrome is typically confirmed through genetic testing, which is often prompted by a personal or family history suggestive of the condition. Clinical criteria, such as the Amsterdam II criteria or revised Bethesda guidelines, can help identify individuals who would benefit from genetic testing, though these are now often complemented or superseded by universal tumour testing [PMID:31454153].
In the UK, suspicion of Lynch syndrome often arises when a person develops an early-onset colorectal or endometrial cancer, or when tumour testing (e.g., immunohistochemistry for MMR proteins or microsatellite instability testing) indicates a potential deficiency in the mismatch repair system. These tumour tests can indicate which gene might be involved, guiding subsequent germline genetic testing on a blood sample. Referrals for genetic testing are generally made by a consultant or GP to a regional Clinical Genetics service, aligning with the NHS Genomic Medicine Service. The relevant NHS R-codes for Lynch syndrome testing facilitate this process.
Management & lifestyle
Management for individuals diagnosed with Lynch syndrome focuses on regular surveillance to detect cancers early and, in some cases, risk-reducing interventions. These strategies are crucial due to the increased lifetime cancer risks. specific management plans are highly individualised.
For colorectal cancer, surveillance typically involves regular colonoscopies, often starting in the early 20s, to identify and remove precancerous polyps. For endometrial cancer, annual screening might include transvaginal ultrasound and endometrial biopsies. Surveillance for other associated cancers, such as those of the stomach or urinary tract, may also be recommended based on family history and individual risk factors.
Risk-reducing surgery, such as prophylactic hysterectomy and oophorectomy for women who have completed childbearing, may be considered to reduce the risk of endometrial and ovarian cancers. Aspirin use is also being investigated as a potential chemopreventative agent for colorectal cancer in individuals with Lynch syndrome [PMID:32296061]. All management decisions are made in consultation with specialist clinicians, including oncologists, gastroenterologists, and clinical geneticists, within the NHS framework.
UK care pathway
In the UK, individuals suspected of having Lynch syndrome are typically referred to a regional NHS Clinical Genetics service. This referral often comes from a GP or a specialist consultant, particularly if there's a strong family history of Lynch-associated cancers or if tumour testing results suggest a mismatch repair deficiency. Genetic counsellors within these services provide essential support and information, helping individuals understand the implications of genetic testing and diagnosis.
Genetic testing for Lynch syndrome is available through the NHS Genomic Medicine Service, with specific R-codes (e.g., R180 for inherited colorectal cancer, R213 for inherited endometrial cancer) guiding the testing process. Following a diagnosis, individuals are usually entered into a personalised surveillance programme coordinated by specialist multidisciplinary teams, often involving gastroenterologists, gynaecologists, and oncologists, to ensure timely and appropriate care.
Frequently asked questions
What is the likelihood of developing cancer if I have Lynch syndrome caused by an MLH1 variant?
Having a pathogenic MLH1 variant significantly increases your lifetime risk of developing certain cancers, especially colorectal and endometrial. For colorectal cancer, the risk is typically 40-60%, and for endometrial cancer, it's 30-60%. It's important to remember this is an increased risk, not a certainty, and regular surveillance can help with early detection.
If my parent has Lynch syndrome, what does that mean for me and my children?
If one of your parents has Lynch syndrome, you have a 50% chance of inheriting the pathogenic gene variant. If you inherit it, you are at an increased risk of developing associated cancers and could pass the variant on to each of your own children with a 50% chance for each child. Genetic counselling can help you understand these risks fully.
Can Lynch syndrome be prevented?
Lynch syndrome itself is an inherited condition and cannot be prevented. However, the cancers associated with Lynch syndrome can often be detected early or even prevented through regular screening (like colonoscopies) and, in some cases, risk-reducing surgeries or medications. These proactive measures can significantly improve outcomes.
What kind of regular check-ups will I need if I have Lynch syndrome?
Your check-up schedule will be personalised, but typically includes regular colonoscopies, often starting in your early 20s, to screen for colorectal cancer. Women may also have regular gynaecological surveillance for endometrial cancer. Additional screenings may be recommended for other cancers depending on your specific risks and family history.
Where can I get support if I or a family member is diagnosed with Lynch syndrome in the UK?
In the UK, your NHS Clinical Genetics service is a primary point of contact for support and information. Genetic counsellors can provide detailed explanations and emotional support. Patient advocacy groups also offer valuable resources and community support.
References
- Buchanan DD, Alvarez R, Mahmood K. Germline MLH1 c.-42 C > T is a likely pathogenic variant predisposing to a reduced-penetrance/modified Lynch syndrome phenotype featuring MLH1-methylated cancers. Familial cancer. 2026. PMID: 41619042