Lynch syndrome (MSH6)

Overview

Lynch syndrome, sometimes referred to as hereditary non-polyposis colorectal cancer (HNPCC), is a common inherited cause of cancer. It is characterised by an increased lifetime risk of developing certain types of cancer, most notably colorectal cancer and endometrial (womb) cancer [PMID:33651114]. Other cancers, such as ovarian, stomach, urinary tract, and brain cancers, may also occur with increased frequency. Lynch syndrome is caused by pathogenic variants in genes involved in DNA mismatch repair (MMR), with MSH6 being one of these key genes.

While individuals with Lynch syndrome have a higher cancer risk, it is important to remember that not everyone with the condition will develop cancer. The risks can vary depending on which gene is affected, as well as other genetic and lifestyle factors. Early identification through genetic testing allows for enhanced surveillance and risk-reduction strategies, which can significantly improve outcomes. Recognition of Lynch syndrome is crucial for affected individuals and their families to manage these risks proactively.

Symptoms & clinical features

The symptoms of Lynch syndrome (MSH6) are primarily related to the development of cancer. As the condition itself does not cause specific symptoms, the signs that might prompt investigation are those of the associated cancers. For colorectal cancer, these can include changes in bowel habits, blood in the stool, abdominal pain, unexplained weight loss, or anaemia [PMID:33651114].

For endometrial cancer, symptoms may involve abnormal vaginal bleeding, such as bleeding between periods, after menopause, or unusually heavy periods. Other potential cancers linked to Lynch syndrome (MSH6) could present with a variety of symptoms depending on the organ affected, such as indigestion or stomach pain for gastric cancer, or urinary changes for urinary tract cancers. Importantly, these symptoms are common and can be caused by many other conditions. The key feature in Lynch syndrome is often the earlier age of cancer onset and the occurrence of multiple primary cancers in an individual or family.

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Affected organs

Lynch syndrome (MSH6) primarily affects organs susceptible to cancer development due to impaired DNA repair. The most frequently affected organs are the large bowel (colon and rectum) and the uterus (endometrium). This leads to an increased risk of colorectal cancer and endometrial cancer, respectively [PMID:33651114].

Beyond these, there is also an elevated risk, albeit generally lower, for cancers in other organs. These can include the ovaries, stomach, small bowel, urinary tract (kidney, bladder, ureters), brain, and sebaceous glands (skin). The specific cancer risks can vary depending on the particular gene variant involved in Lynch syndrome. For MSH6, the risks for endometrial and ovarian cancer tend to be notably higher compared to some other Lynch syndrome genes.

Colon

Elevated colorectal cancer risk

Cellular impact

Mechanism at cellular level

Risks & severity

The severity of Lynch syndrome (MSH6) relates to the increased lifetime risk of developing certain cancers and the potential for earlier cancer onset. While the exact prevalence of Lynch syndrome is not well established, it is recognised as a significant cause of inherited cancer. For individuals with pathogenic MSH6 variants, the estimated lifetime risk for colorectal cancer is generally considered to be lower than for MSH2 or MLH1 variants, but still substantially elevated compared to the general population [PMID:27083111].

The lifetime risk for endometrial cancer in individuals with MSH6 pathogenic variants is also significantly increased, and may be higher than the colorectal cancer risk in some studies [PMID:35773822]. Other cancer risks, such as for ovarian, gastric, and urinary tract cancers, are also elevated. The age of onset for these cancers tends to be earlier than in the general population, often occurring before the age of 50. Penetrance for MSH6 variants can be variable, meaning that not everyone with a pathogenic variant will develop cancer, reflecting a less penetrant phenotype compared to other Lynch syndrome genes. Regular surveillance and risk management are crucial for individuals identified with this condition.

Genetic causes

Lynch syndrome is caused by pathogenic variants in genes responsible for DNA mismatch repair (MMR). These genes include MLH1, MSH2, MSH6, PMS2, and EPCAM. In the case of Lynch syndrome (MSH6), the condition results from specific genetic changes within the MSH6 gene.

The MSH6 gene provides instructions for making a protein that is a key component of the DNA mismatch repair system. This system acts like a cellular proofreader, identifying and correcting small errors that occur when DNA is copied during cell division. Specifically, the MSH6 protein often pairs with the MSH2 protein to form a complex (MutSα) that recognises mismatched bases and small insertions or deletions in the DNA [PMID:27083111]. Pathogenic variants in MSH6 impair the function of this protein, leading to a faulty DNA repair system. When DNA repair is compromised, errors accumulate, increasing the likelihood of cells becoming cancerous over time.

• MSH6
  mutS homolog 6
  The MSH6 gene provides instructions for a protein critical to DNA mismatch repair, playing a vital role in correcting errors that occur during DNA replication.

Inheritance pattern

Lynch syndrome (MSH6) is inherited in an autosomal dominant pattern. This means that only one copy of the MSH6 gene needs to have a pathogenic variant for an individual to have the condition. An affected individual has a 50% chance (one in two) of passing on the pathogenic variant to each of their children, regardless of the child's sex.

Family members who do not inherit the pathogenic variant will not develop Lynch syndrome and cannot pass it on to their own children. However, it is important to remember that individuals can carry a pathogenic variant without necessarily developing cancer themselves, due to variable penetrance. For relatives of an affected individual, genetic counselling and testing can help clarify their own risks and inform appropriate surveillance strategies.

Diagnosis & testing

The diagnosis of Lynch syndrome (MSH6) is confirmed through genetic testing. This testing is typically offered to individuals who meet specific clinical criteria, often based on family history of certain cancers (e.g., Amsterdam criteria or revised Bethesda guidelines) or tumour characteristics (e.g., microsatellite instability or immunohistochemistry staining for MMR proteins) [PMID:33651114]. Genetic testing usually involves a blood sample, which is analysed to look for pathogenic variants in the MSH6 gene.

Referral for genetic testing is usually made by a clinician, such as a gastroenterologist, gynaecologist, or oncologist, in consultation with a clinical genetics service. In the UK, this process aligns with the NHS Genomic Medicine Service (GMS) pathways. Relevant R-codes within the GMS typically cover testing for Lynch syndrome genes, including MSH6, allowing for comprehensive panel testing where appropriate. A genetic counsellor will often discuss the implications of testing, help interpret results, and provide ongoing support.

Management & lifestyle

Management for individuals diagnosed with Lynch syndrome (MSH6) focuses on early detection of associated cancers and, in some cases, risk-reducing interventions. It is crucial to have a personalised management plan developed in consultation with a multidisciplinary team of specialists, including gastroenterologists, oncologists, gynaecologists, and clinical geneticists.

Surveillance typically includes regular colonoscopies, often starting in the twenties or early thirties, to detect and remove polyps before they become cancerous [PMID:35773822]. For women, annual gynaecological examinations, endometrial biopsies, and transvaginal ultrasound may be recommended to screen for endometrial and ovarian cancers. Risk-reducing surgery, such as prophylactic hysterectomy and bilateral salpingo-oophorectomy (removal of the uterus and ovaries), may be an option for women who have completed their families and wish to significantly reduce their risk of gynaecological cancers. Lifestyle modifications, such as maintaining a healthy weight, regular physical activity, and a balanced diet, may also contribute to overall health and cancer prevention, although their specific impact on Lynch syndrome-related cancers is still an area of ongoing research. All management decisions should be discussed with a healthcare professional.

UK care pathway

In the UK, individuals suspected of having Lynch syndrome (MSH6) are typically referred to a clinical genetics service through the NHS Genomic Medicine Service (GMS). This pathway ensures access to specialist assessment, genetic counselling, and diagnostic genetic testing. The GMS uses specific R-codes to guide appropriate testing for inherited cancer predisposition conditions, including those related to Lynch syndrome genes like MSH6.

Following a diagnosis, individuals are supported by a clinical genetics team and genetic counsellors who provide information, discuss inheritance patterns, and help coordinate appropriate cancer surveillance and management plans within the NHS. Genetic counselling is also available for family members who may be at risk of inheriting the MSH6 pathogenic variant.

Related conditions

Lynch syndrome encompasses several conditions caused by pathogenic variants in different DNA mismatch repair genes. While Lynch syndrome (MSH6) has distinct features, other forms of Lynch syndrome, such as those caused by pathogenic variants in MLH1, MSH2, or PMS2, share similar cancer risks but may have varying penetrance and spectrum of associated cancers. Attenuated familial adenomatous polyposis (AFAP) can sometimes be considered in the differential diagnosis due to an increased risk of colorectal polyps, although its genetic basis (APC gene) and typical presentation differ. Hereditary breast and ovarian cancer syndrome (HBOC), caused by BRCA1 or BRCA2 pathogenic variants, also involves an increased cancer risk but primarily affects breast and ovarian cancers, making it distinct from Lynch syndrome.

• Constitutional mismatch repair deficiency
  Cancer Predisposition
  Shares 1 gene

Frequently asked questions