The diverse molecular profiles of lynch syndrome-associated colorectal cancers are (highly) dependent on underlying germline mismatch repair mutations

[Display omitted] •The molecular profile of Lynch carcinomas is highly heterogeneous.•Care of Lynch patients should be specifically optimized for each subgroup.•The proportion of WNT and RAS signalling pathway mutations differs per Lynch subgroup.•APC and CTNNB1 mutations influence all three carcinogenesis pathways in LS.•LS CRS develop from MMR-deficient crypts or from MMR-proficient/deficient adenomas. Lynch syndrome (LS) is a hereditary cancer syndrome that accounts for 3% of all new colorectal cancer (CRC) cases. Patients carry a germline pathogenic variant in one of the mismatch repair (MMR) genes (MLH1, MSH2, MSH6 or PMS2), which encode proteins involved in a post-replicative proofreading and editing mechanism. The clinical presentation of LS is highly heterogeneous, showing high variability in age at onset and penetrance of cancer, which may be partly attributable to the molecular profiles of carcinomas. This review discusses the frequency of alterations in the WNT/B-CATENIN, RAF/MEK/ERK and PI3K/PTEN/AKT pathways identified in all four LS subgroups and how these changes may relate to the ‘three pathway model’ of carcinogenesis, in which LS CRCs develop from MMR-proficient adenomas, MMR-deficient adenomas or directly from MMR-deficient crypts. Understanding the specific differences in carcinogenesis for each LS subgroup will aid in the further optimization of guidelines for diagnosis, surveillance and treatment.