Population-based screening for Lynch syndrome in patients with colorectal cancer: implementing the NICE diagnostic pathway

Background Lynch syndrome (LS) is defined by having a pathogenic constitutional variant affecting one of the four mismatch repair (MMR) genes: MSH2, MLH1, MSH6 or PMS2. In 2017, National Institute for Health and Care Excellence guidelines recommended screening all newly diagnosed colorectal cancer (CRC) patients for possible LS. We assessed referral pathways to molecular pathology and onwards to clinical genetics from our regional services covering the 1.9 million population of Northern Ireland, following implementation of this guidance, and resultant diagnostic rates of LS.Methods CRCs diagnosed between November 2019 and February 2022, and referred for molecular testing, were identified for this audit. Samples which were microsatellite instability-high (MSI-H) and BRAF WT were subsequently referred to the Clinical Genetics service for constitutional MMR gene testing.Results A total of 1949 CRCs were tested for MSI status corresponding to 97.6% of the population. Of these, 239 (12.3%) were classified as MSI-H and 113 of these 239 tumours (47.2%) were BRAF wild type, prompting referral for germline testing. 102 of the 113 cases (90.3%, or 5.8% of the total) were referred to clinical genetics, revealing 24 patients with constitutional variants. This equates to 1.2% of the total cohort of 1949 patients initially screened by MSI testing. Predictive testing yielded a further 33 family relatives with LS.Conclusions To the best of our knowledge, we are the first region in the UK to demonstrate universal MSI testing for CRC that has captured over 95% of the CRC population, with 90% onward referral rate to clinical genetics for constitutional testing yielding comprehensive detection of LS at the population level, for this patient group presenting with CRC.