Guidance
2 The diagnostic tests
Clinical need and practice
2.1 Lynch syndrome is an inherited genetic condition associated with an increased risk of several cancers, particularly endometrial and colorectal cancer. It is caused by mutations in, or near, the DNA sequence of mismatch repair (MMR) genes. If a person has Lynch syndrome, these mutations are in every cell of their body and can be identified by genetic testing of non-tumour tissue. This testing shows mutations inherited by a person in their 'germline' instead of those that are only in cancerous tissue.
2.2 Identifying Lynch syndrome at the point of endometrial cancer diagnosis could:
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prevent other cancers in people with Lynch syndrome (such as colorectal cancer) through increased surveillance and strategies to reduce risk
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help to identify relatives with Lynch syndrome, to reduce their risk of Lynch syndrome-associated cancers or increase early detection of cancer
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help relatives diagnosed at an early age to consider family planning and, if they wish, have risk-reducing interventions, for example, a hysterectomy.
2.3 Currently, testing for Lynch syndrome in people diagnosed with endometrial cancer is often not done, or may only be done for people with an identified risk factor for the condition. This could be age at diagnosis or a family history of Lynch syndrome-related cancers. Clinical experts commented that even if tumour testing for potential Lynch syndrome is routinely done, a referral to clinical genetics services may still be needed if the tumour tests do not indicate Lynch syndrome but a person has an identified risk factor that suggests the condition is likely.
The interventions
2.4 Most endometrial cancers do not develop because of Lynch syndrome (sporadic cancer). Tests done on endometrial tumour tissue can help identify how likely it is that the cancer happened because a person has Lynch syndrome and if genetic testing of non-tumour tissue should be done to check for the condition.
2.5 Testing for microsatellite instability (MSI) in endometrial tumour tissue or testing for loss of MMR proteins using immunohistochemistry (IHC), or doing both, can show potential Lynch syndrome. But both tests can give false positive results for potential Lynch syndrome. So, another test (MLH1 promoter hypermethylation testing) can be done on tumour tissue if MSI is present or if IHC shows loss of MLH1 protein. If MLH1 promoter hypermethylation is present in the tumour the cancer is likely to be sporadic, instead of being caused by Lynch syndrome.
2.6 This assessment includes different combinations of IHC, MSI and MLH1 promoter hypermethylation testing done on endometrial tumour tissue to see if the cancer is likely to have been caused by Lynch syndrome.
2.7 All strategies include final genetic testing of non-tumour tissue to make a diagnosis of Lynch syndrome (germline testing). Sometimes this testing can show changes in the sequences of the MMR genes, but it is not known if these changes cause Lynch syndrome or not. These are called variants of uncertain significance.