The results of the following investigations in colorectal and/or endometrial tumour tissue significantly influence the likelihood of detecting a heritable pathogenic variant in a MMR gene and if ordered should ideally be done prior to germline testing:
- Immunohistochemistry (IHC) for the MMR proteins MLH1, MSH2, MSH6 and PMS2.
- Assessment of microsatellite repeats (microsatellite instability or MSI testing) can be useful in detecting missense variants not detected by IHC.
- Studies for detection of the BRAF V600E pathogenic variant in colorectal cancer tissue if loss of MLH1/PMS2 is identified.
- MLH1 promoter methylation studies if loss of MLH1/PMS2 is identified.
- Promoter methylation studies of the other MMR genes.
There is evidence to support routinely screening colorectal and endometrial cancers using MMR immunohistochemistry. The exact age threshold is debated. Cancer Council Australia guidelines recommend universal MMR immunohistochemistry regardless of age (CRC-wiki link 1, CRC-wiki link 2, HGSA COSA position statement). An Australian analysis demonstrated MMR immunohistochemistry in individuals diagnosed with colorectal cancer (CRC) under the age of 70 years resulted in higher Lynch syndrome case detection compared to no screening, at a reasonable cost.r In an Australian study of unselected endometrial cancer cases, universal MMR IHC testing detected Lynch syndrome in only individuals initially diagnosed under the age of 70 years.r
MMR immunohistochemistry may also be considered in other isolated early onset tumours in the Lynch syndrome tumour spectrum.
Whilst the pattern of immunohistochemical loss of MMR protein will give an indication of which gene is most likely to have a pathogenic variant, panel testing of all MMR genes is now readily available (see flow chart).