Molecular assessment of colorectal cancer through Lynch syndrome screening

Since 2017, the National Institute for Health and Care Excellence (NICE) has recommended molecular testing of all patients with newly diagnosed colorectal cancer (CRC) to identify those with suspected Lynch syndrome who should be referred to clinical genetics for germline testing. The pathway involves firstly determining the mismatch repair (MMR) expression status by immunohistochemistry (IHC) or performing microsatellite instability testing. This may be followed by BRAF V600E mutation testing and then MLH1 promoter hypermethylation analysis depending on the result. This approach identifies patients that are most likely to have underlying germline mutations in the MMR genes as opposed to somatic causes of deficient MMR. Here we demonstrate a case with loss of MLH1 protein expression and discuss the subsequent testing strategy according to NICE guidance.