Lynch syndrome is an inherited genetic disorder that increases your chance of having certain cancers, across your lifetime. People with Lynch syndrome usually develop cancer at a younger age. If you are diagnosed with Lynch syndrome your close family members are at greater risk of having it too.
Lynch syndrome is thought to be Australia's most common inherited cancer risk. Someone with Lynch syndrome has a one in two chance of passing it on to their children. Men and women have an equal chance of inheriting Lynch syndrome. It is caused by mutations in genes that normally repair DNA damage. When these genes don’t work properly, cells can accumulate errors in their DNA and grow uncontrollably, causing cancer.
Lynch syndrome is associated with a higher risk of developing more than one type of bowel cancer. It also increases the risk of developing other cancers including endometrial (uterine), ovarian, stomach, liver and gallbladder, kidney, urinary tract, pancreatic, prostate, brain and skin cancers.
It is important to note that although someone who has inherited a Lynch syndrome-related faulty gene is more likely to develop cancer, but it does not mean you will definitely develop cancer. On the other hand, there are many people who do not have any Lynch syndrome related faulty genes and develop cancer.
What causes Lynch syndrome?
Our bodies are made up of trillions of cells. Almost every cell has a nucleus (a sac in the middle of the cell) containing a complete set of genes. Genes are the chemical instructions that tell your body how to make all the different parts it needs to function.
Inside the nucleus are structures called chromosomes. Tightly packaged up inside chromosomes is our DNA. Genes are short sections of DNA. About two per cent of our DNA carries the instructions to make all the proteins our body needs to function. The remaining DNA works behind the scenes controlling how our genes work.
Our cells have a lifespan – they get old and die off. They replace themselves with new cells. To do this they make a copy of themselves and then divide into two. Each time a cell divides, it copies its chromosomes and DNA and sometimes, small copying mistakes can occur, called mutations or variants.
This is perfectly natural and happens to everyone. Usually, our body repairs these mutations or else gets rid of the damaged cells.
Our body repairs these mutations through inherited genes known as mismatch repair genes. In families with Lynch syndrome, one of these mismatch repair genes has a fault which is passed down through from parent to child.
What are mismatch repair genes (MMR)?
There are several different mismatch repair genes which are responsible for correcting mutations in our DNA. If you have inherited a faulty version of any one of five possible mismatch repair genes, small errors in your DNA go unrepaired and this can increase your chance of having cancer. These errors lead to a condition called microsatellite instability (MSI) – where small, repeated sections of DNA accumulate errors. MSI in DNA increases the risk of a person developing certain types of cancer.
Everyone who has bowel or endometrial cancer surgery will have their tumour investigated by a pathologist who will examine cells in the tissue through a microscope. This is to make sure all the cancerous cells have been completely removed and to provide more details about the type of cancer. Each cancer has a distinct signature or patterns of cell changes or mutations. If the pathologist considers the cancer may be due to Lynch syndrome, they will undertake further testing.
If you have bowel or endometrial cancer and you are under 50, your surgeon may flag this and ask the laboratory to test your sample for mutations in the mis-match repair genes associated with Lynch syndrome. If your tumour or polyp is found to have a mutation in one of these genes, this does not necessarily mean you have Lynch syndrome, as the mutation could have occurred in your tumour or polyp for the first time. You will need further testing to work out whether you have Lynch syndrome. If you have a family history of cancer at an early age it is important to talk to your doctor about testing for Lynch Syndrome. See “Any more to know” section at the end of this page.
Types of tests
The testing process usually begins with your tumour being sent to the lab for one or both of two tests, immunohistochemical (IHC) and/or microsatellite instability (MSI) testing. These look for changes in your tumour which can be associated with Lynch syndrome. If either of these tests show changes that suggest Lynch syndrome you will be advised to have further genetic testing to see if you have Lynch syndrome.
Microsatellite instability (MSI) testing
MSI refers to changes in DNA that result from the repair system not working properly. Microsatellites are small, repeated patterns in your DNA. Normally, your body fixes any mistakes in this DNA when cells divide. But if the repair system does not work correctly, errors in DNA replication can occur and this is called microsatellite instability.
People with Lynch Syndrome are more likely to have tumours with microsatellite instability because the genes that repair the DNA do not work and errors can occur during DNA replication. About 90 per cent of bowel cancer tumours caused by Lynch syndrome have microsatellite instability, but only about 15 per cent of sporadic bowel cancer tumours have this change.
Immunohistochemistry (IHC) testing
Immunohistochemical staining (IHC) has now largely replaced the MSI test. In IHC, the tumour tissue is stained and then examined under a microscope.
Genes work by making proteins and IHC detects the proteins made by the mismatch repair genes. If any of these proteins are missing it means you have a faulty version of the corresponding gene, and it is not working properly. However, this test cannot tell whether the faulty gene is only in the tumour or polyp tested or in every cell in your body (as with people who have Lynch syndrome). It is estimated that about 80 percent of people with Lynch syndrome have abnormal IHC results.
IHC is more commonly used as the first screening test because it directly shows which mismatch repair gene proteins are missing. MSI testing is still used when IHC results are inconclusive or when proteins are present but not working.
Germline genetic testing
If the result of MSI and/or IHC testing of the tumour suggests Lynch syndrome, you will need to have genetic testing to see if you have Lynch syndrome. Before you do this, you will need to have genetic counselling.
Genetic testing involves analysing the DNA in a blood sample to detect specific faulty mismatch repair genes that are known to cause Lynch syndrome. These faults are called germline mutations. Germline refers to cells that develop into eggs and sperm (also known as germ cells). These cells contain the genetic material that is passed on from one generation to the next. If there is a gene fault in one of these cells and that egg or sperm is used to make a baby, that baby will have the gene fault in every cell in their body.
Usually, when bowel or endometrial cancer is being investigated, five genes are tested through a process called genetic sequencing. These are: MLH1, MSH2, MSH6, PMS2 and EPCAM.
Other genes may be tested. For more on genetic testing see Inherited cancer risk - bowel and endometrial cancer.
Sample
Tissue – IHC and MSI are performed on samples of tumour or polyp tissue.
Blood – germline genetic testing is performed using a blood sample.
Preparation
If the MSI or IHC results on the tumour detect a mutation in the mismatch repair genes, genetic counselling is recommended before you go on to have genetic testing.
Genetic counselling
It is important that you have genetic counselling before you give your blood sample for genetic testing so that you fully understand the implications of having a positive, negative or inconclusive gene result. A diagnosis of Lynch syndrome can have lifelong impacts for you and your family.
Microsatellite instability (MSI) testing results Result Meaning Possible interpretation Microsatellite stable No markers show instability Indicates normal gene function; less likely to be Lynch syndrome-related. MSI-Low Instability in one marker May indicate partial gene deficiency; less commonly associated with Lynch syndrome. MSI-High Instability in two or more markers Suggests faulty repair genes; common in Lynch syndrome and some sporadic cancers. Only about 20 percent of people with abnormal MSI or IHC results have Lynch syndrome. That’s why genetic counselling and testing are so important they help confirm the diagnosis and guide family screening decisions.
| IHC testing results | |
| IHC pattern | Possible Interpretation |
| Loss of MLH1 and PMS2 | Likely MLH1 deficiency - may be sporadic or Lynch-related. |
| Loss of MSH2 and MSH6 | Suggests MSH2 deficiency - often Lynch syndrome. |
| Isolated loss of MSH6 | Indicates MSH6 mutation. |
| Isolated loss of PMS2 | Indicates PMS2 mutation. |
| All proteins present | MMR system likely intact. |
Reading your genetic test report
For more on genetic test results see: Inherited cancer risk - bowel and endometrial cancer.
Which gene is affected?
If you have a fault on a mismatch repair gene your results report will show which of the genes is affected. It is important to know this because each gene is associated with different rates of cancer in different parts of the body. This will impact on the way you will manage your health in future. The details of your results and future cancer screening will be explained to you by the Genetic Counsellor.
Managing your health with Lynch syndrome
If you have a diagnosis of Lynch syndrome you will need to work with your doctors to develop a management plan. This will set out the routine tests you should have, and how often you need to have them, in order to detect any cancer that develops early.
Family testing
If you are diagnosed with Lynch syndrome your close relatives will be advised to have genetic counselling to discuss testing. If a faulty repair gene is found in you, there is a 50% chance that a first-degree relative (parent, sibling, and child) may also carry the same mutation.
Genetic counselling plays an important role in reviewing your family history and the number of cancers, explaining what a positive or negative test result means and discussing options for predictive testing in relatives.
Your Genetic Counsellor or doctor with help you decide your level of risk. Genetic counselling is essential not just for testing, but for emotional support, reproductive, and family implications.
The choice of tests your doctor makes will be based on your medical history and symptoms. It is important that you tell them everything you think might help.
You play a central role in making sure your test results are accurate. Do everything you can to make sure the information you provide is correct and follow instructions closely.
Talk to your doctor about any medications you are taking. Find out if you need to fast or stop any particular foods or supplements. These may affect your results. Ask:
Pathology and diagnostic imaging reports can be added to your My Health Record. You and your healthcare provider can now access your results whenever and wherever needed.
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