Written by: Dr Pauline Skarrott. 

Always ask your own clinical geneticist, genetic counsellor or GP if you need advice on your own situation.


Lynch syndrome (LS) is an inherited predisposition to some cancers. It was previously known as HNPCC or hereditary non-polyposis colorectal cancer. This latter term does not adequately describe the different cancers that are involved and so the name of the person who has done so much work on this subject, Dr Henry T Lynch from America is now firmly attached to the syndrome.

“The eponymous Dr Henry Lynch is internationally recognised for his contributions to the discovery of the syndrome, his descriptions of the natural history, raising awareness by publishing and speaking and his graciousness and support for organisations that work directly with individuals and families with Lynch syndrome”(1)

What Are Genes?

Genes are the building blocks of material that we inherit from our parents. They sit on all of the chromosomes in each cell of our body and are passed from both of our parents so that we have a full complement of genes when we are born. Each chromosome is made up of lots of genes and all the genes are made up of DNA (deoxyribonucleic acid) – the Lego bricks of our cells’ replication system.


Our body depends upon a reliable duplication in each of its cells, otherwise, faults can happen in the workings of that cell and its successors. If that happens repeatedly, errors can turn into precancerous changes. Faults that occur in the gene can be tolerated if a second parent has a gene that somehow cancels its actions out. But some medical conditions linked to dominantly inherited genes prevent the other parent’s genes putting things right.

Lynch Syndrome

The mismatch repair system in the cell normally corrects mistakes when the DNA is being replicated. This prevents cancers starting. If you have Lynch Syndrome, these errors happen more often in cells all over the body and that is why LS is linked to cancers in many different organs.

Diagram 2. Autosomal dominant pattern of inheritance

Lynch syndrome is inherited in an autosomal dominant manner which means it is not sex-linked and it is passed on directly from parent to child without skipping generations. Each child has a 50% chance of inheriting the condition. Each child that is born to a parent with Lynch syndrome has an equal 50:50 chance of inheriting it. For example, just because 4 children have it does not mean that the 5th born child has less of a chance (or more chance) of having LS. The odds are still 50%.


Both sexes can have Lynch syndrome and it may pass to any of their children. If none of their children has LS, there is no chance that it will pass to any of their grandchildren. It does not skip generations.

Lynch syndrome is caused by mutations in one of the following genes: MLH1, MSH2, MSH6, PMS2 and EPCAM. The first four are genes that produce MMR proteins and the last one, EPCAM is an alteration that behaves likes an MMR gene, causing Lynch syndrome.

“70%-90% of Lynch syndrome is caused by MLH1 and MSH2 mutations with the remaining 10%-30% divided equally between MSH6 and PMS2. Approx 3% of Lynch syndrome is caused by deletions in the EPCAM gene” (1)


Recent research, yet to be published is suggesting the spread of the different genes in Lynch syndrome might be evener.

Diagram 3. Position of MSH2 gene on a chromosome

Cancer cells under a microscope

Why People With MMR Genes Get Cancer

Various parts of the body have cells that replicate frequently. They are particularly vulnerable to mismatch repair (MMR) faults in the genes of their cells. This only occurs in a few cells – not every single cell in that organ. However, in organs where the cells have a fast turnover and are being replaced and duplicated very frequently, things can go awry and cancerous changes can start. Initially, this is just changes in the DNA but as these are replicated, cells become abnormal and “dysmorphic”. These are oddly shaped cells that behave abnormally and will multiply tens of thousands of times over. A cancerous area is born.


This area, which contains all the rogue cells, now behaves in the typical manner of cancer. The normal surrounding cells are no longer able to prevent the spread of the cancerous growth. It will grow into and through layers of the organ and then through into the adjacent tissues.


Eventually, as with other types of cancer, cells break off or metastasise into lymph nodes and through the vascular system to other parts of the body.

Some Beneficial  Characteristics  Of Lynch Syndrome

There is evidence that, in the early stages of Lynch syndrome cancers, some characteristics of them actually improve the prognosis. That is despite the fact that they grow quicker and change from precancerous to cancers by missing some steps out.


Certain cells that are characteristic of LS cancers such do in fact, help to attack cancer. This is why the mortality statistics for some LS cancers such as colorectal cancer are better in some studies than ordinary sporadic colorectal cancers of a similar stage.

 Why Does Lynch Syndrome Only Affect Certain Parts Of The Bofy



“Lynch syndrome exhibits characteristic features of cancer disposition syndrome, including elevated risks of certain cancers, earlier onset, and high rates of multiple primary cancers and the absence of typical risk factors. Cancers associated with Lynch syndrome include colorectal, endometrial, ovarian, stomach, hepatobiliary (liver and bile), urinary and kidney, small bowel, brain/central nervous system and sebaceous cancers.”(1). Pancreas, breast and prostate are now included.


Cancers caused by faults in MMR genes are typically those with epithelial cells. These are the very thin cells that line the surface of organs and are particularly common in organs that are in contact with body fluids, the outside surface of the body or the inner surface of organs that have a large surface area. You may be able to see that the cancers that are listed below follow that general rule.

Lynch syndrome cancers include the following:


Colon and rectum

The whole gastrointestinal tract is lined with thin, smooth epithelial cells. These replicate extremely frequently and the colon and rectum are the most common cancer in Lynch syndrome. In ordinary or “sporadic” CRC cancers, they occur more frequently on the left-hand side of the colon. In LS they are more evenly spread throughout the colon.


Endometrial cancer (uterus)

The inner lining of the uterus regularly builds up and then is shed every month. Unlike ordinary endometrial cancers, LS cancers occur more frequently at the outlet of the uterus.


Kidneys, ureters and bladder (uroepithelial cancers)

These organs are lined with epithelial cells and the convoluted areas within the kidneys produce a large area in which MMR faults can arise. In Lynch syndrome, the kidneys are affected by cancers to the highest degree, followed by the ureters, then the bladders.



The ovary is difficult to screen and therefore women must be aware of ovarian cancer symptoms or elect to have them removed.

Younger onset of Lynch syndrome cancers

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Younger onset of Lynch syndrome cancers


The fact that Lynch syndrome cancers occur at least (on average) ten years younger than in other people is a feature of the syndrome. For example, endometrial cancer in women is, on average at 60 years in the general population but in Lynch syndrome, the average age of onset is 40 years. Colorectal cancer usually happens at 70 years or beyond but LS CRC occurs, on average at 43 years, often earlier.


The Different  Mutated Genes In Lynch Syndrome


Mutations of each of the four Lynch mismatch repair genes MLH1, MSH2, MSH6 and PMS2 can cause Lynch syndrome. Because they are dominantly inherited, it only needs one parent with the condition to pass on Lynch syndrome.


Rarely, if two parents with Lynch syndrome have a child, that person will have a much higher risk of cancers at an earlier age. It may be a devastating pattern of illness – often multiple colorectal cancers before the age of 20yrs and other early and aggressive cancers.



Some families do have the younger onset of cancers that are not caused by a “double dose” of MMR gene mutations. In these families, there might be an additional gene that makes cancer more likely.


The EPCAM gene is not a mismatch repair gene. It is found further along from the MSH2 gene and it has two different effects. In some people, it just “switches on” the MSH2 gene and the way in which this happens only causes an increase in colorectal cancer and not the other cancers. The second way is that the EPCAM deletion stops the MSH2 gene from working, in which case the MSH2 cancer risks are all present.


Each of the mutated MMR genes has a different effect on the people who carry them. When research was done on LS at first, the individual genes were not distinguished and this gave some very varied results when different populations were studied. For example, when Lynch syndrome carriers were studied in two different countries, it was found that, as an example, the incidence of colorectal cancer was very different in each because there were more families with MSH6 in one group. Now, when different populations of Lynch syndrome carriers are studied, the difference between sexes, gene types and whether they come from disease registries are taken into account.


Age Of Onset Graph


It may seem as if the advice given by genetic clinics is different to what appears from the incidence and age of onset figures for your gene. This is because the risk of cancer does not rise with age in a straight line. It may stay very low for ten or twenty years and then suddenly rise up quickly at say, 40 years.


The graph below shows this. It shows why a bald figure of 70% risk by the age of 70 years can give very different figures for the risk at say, 40 years – 40% or 15%. The advice for screening has to be given depending on these graphs.


That is why, for example, women with LS who have MLH1 genome are advised against having endometrial screening until they are 30-35 yrs.


Your Lynch syndrome mutated gene is there with you when you were born. It does not change as you get older and until there is specific gene therapy, there is no treatment that can “get rid of” the gene. It has been inherited from your parents. The possibility of a new Lynch syndrome carrier in the family as a specific mutation is rare but not impossible.


Risks Of Getting Cancer


The risks of getting cancer if you have Lynch syndrome depend on a lot of things and you really must see either a genetic counsellor or a clinical geneticist sort out what your particular risks are and what screening you need. The sections on Lynch syndrome cancers on our website give you information about each but you are an individual and you must get professional advice on this. Our website and facebook pages are just to give you additional support and advice. We want you to feel as though you know more and can understand more of what you are told and can then ask all the questions you would like.


Remember that not everyone who carries an LS gene mutation will get cancer. If 40% of people get cancer by the age of 70 years that means that on average 60% won’t. Age and sex make a big difference to risk, as does the other genes in your body that can affect your susceptibility to cancer. Also, you can reduce your cancer risk by not smoking, keeping a normal weight and maintaining a healthy lifestyle. Treatments such as aspirin helps to prevent the first cancerous changes in the cells. And above all, screening such as regular colonoscopies will help keep any cancerous changes to the minimum.


Cohen, S and Leininger,And in “The genetic basis of Lynch syndrome and its implications for clinical practice and risk management” in Appl Clin Genet 2014;147-158

Published online Jul 22, 2014. doi; 10.2147/TACG.S51483


Lynch HT, et al in “Review of the Lynch syndrome: history, molecular genetics, screening.

differential diagnosis and medicolegal ramifications in Clinical Genetics vol 76; no 1 July


(This is a review article by the ever brilliant Henry Lynch and his team but it is a bit technical. Just skip the bits you don’t understand. Written in his mid-80s! If you have never read any of his research articles – have a look at this and wonder. He is one awesome guy!



Here are some links if you would like a less complicated approach to Lynch syndrome genetics:-

Leaflet from University Hospital Southampton, UK


One from the Regional Genetics Centre, Oxford University Hospitals Trust, UK


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