Mismatch repair (MMR) is a system inside all normal, healthy cells for fixing mistakes in our genetic material (DNA). The system is made up of different specialized chemicals called proteins and the four most common proteins are called MSH2, MSH6, MLH1, and PMS2. A loss of one of these proteins increases the risk of developing cancer. Pathologists order mismatch repair testing to see if any of these proteins are lost in a tumour. If mismatch repair tested has been ordered on your tissue sample, the results will be described in your pathology report.
Each cell in your body contains a set of instructions that tell the cell how to behave. These instructions are written in a language called DNA and the instructions are stored on 46 chromosomes in each cell. Because the instructions are very long, they are broken up into sections called genes and each gene tells the cell how to produce a piece of the machine called a protein.
If the DNA becomes damaged or if it cannot be read accurately, the cell will be unable to produce the proteins it requires to function normally. An area of damaged DNA is called a mutation and mutations are one of the most common causes of cancer in humans. Mismatch repair proteins keep cells healthy and functioning normally by fixing these mutations when they happen.
The four mismatch repair proteins MSH2, MSH6, MLH1, and PMS2 work in pairs to fix damaged DNA. Specifically, MSH2 works with MSH6 and MLH1 works with PMS2. If one protein is lost, the pair cannot function normally.
For most people, cancer develops as a result of both environmental factors (for example smoking) and genetic factors. These tumours are called ‘sporadic’ because we cannot predict exactly which people will develop them and when. Some people, however, inherit genetic changes that put them at a much higher risk of developing cancer. These people are said to have a syndrome.
Lynch syndrome is caused by a genetic change that results in the loss of one of the mismatch repair proteins. Another name for this syndrome is hereditary nonpolyposis colorectal cancer (HNPCC).
The most common genetic changes associated with Lynch syndrome involve the genes that produce MLH1 and MSH2. A small number of people with Lynch syndrome will show genetic changes involving MSH6 and PMS2.
People with Lynch syndrome are at high risk for developing colon cancer at an early age. Women with Lynch syndrome are also at risk for developing ovarian and endometrial cancer at an early age. Other types of cancers associated with Lynch syndrome include stomach, liver, bladder, skin, and brain.
Muir-Torre is a syndrome that is closely related to Lynch syndrome. People with Muir-Torre are at high risk for developing a type of skin cancer called sebaceous carcinoma. These people are also at risk for developing multiple non-cancerous skin tumours called sebaceous adenomas.
The most common way to test for mismatch repair proteins is to perform a test called immunohistochemistry. This test allows pathologists to see if the tumour cells are producing all four mismatch repair proteins.
If the tumour cells are not producing one of the proteins, your report will describe this protein as “lost” or “deficient”. Because the mismatch repair proteins work in pairs (MSH2 + MSH6 and MLH1 + PMS2), two proteins are often lost at the same time.
If the tumour cells in your tissue sample show a loss of one or more mismatch repair proteins, you may have inherited Lynch syndrome and should be referred to a genetic specialist for additional tests and advice.