Molecular biology from bench-to-bedside – Which colorectal cancer patients should be referred for genetic counselling and risk assessment

Abstract Lynch syndrome is associated with deficiency of the mismatch repair genes MLH1, MSH2, MSH6 or PMS2. However, most MLH1 deficient tumours are sporadic in origin, and they can be identified if harbouring a BRAF V600E mutation or hypermethylation of the MLH1 gene promoter. The aim of this study was to validate our previously suggested clinically applicable strategy based on molecular characteristics for identifying which patients to refer for genetic counselling. The strategy was validated in an unselected cohort of 287 colorectal cancer patients. All tumours were tested for MLH1, PMS2, MSH2 and MSH6 protein expression with immunohistochemistry. DNA from MLH1 negative tumours was sequenced for BRAF mutations. If BRAF was wild-type, MLH1 promoter was subsequently analyzed for promoter hypermethylation. Most tumours, 251 (88%), stained positive for all four proteins. Six (2%) had negative MSH2 and one (