Multidisciplinary national guidelines on hereditary colorectal cancer: a central role for molecular testing for the early recognition of Lynch Syndrome

M. Ligtenberg, H. Morreau, H. Gille, R. Sijmons, N. Hoogerbrugge, F. Menko on behalf of the guideline committee
Department of Human Genetics, Radboud University Nijmegen Medical Centre

Over 95% of colorectal cancers of Lynch Syndrome patients and about 15% of sporadic colorectal cancers have a defect in DNA mismatch repair that can be identified by microsatellite instability (MSI) testing and immunohistochemical analysis of mismatch repair proteins. To increase the detection level of Lynch Syndrome, MSI testing initiated by the pathologist has been given a central role in the guidelines. Clinicians inform their patients with probable colorectal or endometrial cancer that pathological analysis may be indicative of hereditary predisposition. Subsequently, pathologists can initiate MSI testing in all newly diagnosed colorectal and endometrial carcinomas diagnosed below age 50 or in cases with a second Lynch-syndrome associated tumor below age 70. The results of these tests are reported in a standard manner in which referral to a clinical geneticist is advised in cases of a positive MSI test, a positive family history or polyposis. Clinical geneticists can initiate molecular analyses to differentiate sporadic MSI positive tumors, which are generally recognized by hypermethylation of the MLH1 promoter, from those that occur as the result of a germline mismatch repair gene mutation. In case no methylation or germline mutation is identified, the patient will be considered as having probable Lynch Syndrome and will be advised similar surveillance as a proven Lynch Syndrome patient. Because of the special expertise needed for the (interpretation) of these molecular analyses and their consequences for both patients and their relatives, concentration of MSI and immunohistochemical testing in laboratories which are part of multidisciplinary cancer family clinics is advised. The full text of the guidelines is given at http://www.oncoline.nl/