A review on the molecular diagnostics of Lynch syndrome: a central role for the pathology laboratory

Lynch syndrome Identification of patients at risk for Lynch syndrome Molecular basis of Lynch syndrome and sporadic MMR-deficient tumours Molecular diagnostics of Lynch syndrome Description of molecular analyses MSI analysis Immunohistochemistry MLH1 promoter hypermethylation assay BRAF mutation analysis Limitations of molecular analyses Conclusions Lynch syndrome (LS) is caused by mutations in mismatch repair genes and is characterized by a high cumulative risk for the development of mainly colorectal carcinoma and endometrial carcinoma. Early detection of LS is important since surveillance can reduce morbidity and mortality. However, the diagnosis of LS is complicated by the absence of a pre-morbid phenotype and germline mutation analysis is expensive and time consuming. Therefore it is standard practice to precede germline mutation analysis by a molecular diagnostic work-up of tumours, guided by clinical and pathological criteria, to select patients for germline mutation analysis. In this review we address these molecular analyses, the central role for the pathologist in the selection of patients for germline diagnostics of LS, as well as the molecular basis of LS.