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AimsScreening all patients newly diagnosed with colorectal cancer (CRC) for possible Lynch syndrome (LS) has been recommended in the United Kingdom since the National Institute for Health and Care Excellence (NICE) released new diagnostics guidance in February 2017. We sought to validate the NICE screening pathway through a prospective regional programme throughout a 5.2-million population during a 2-year period.Methods and resultsPathology departments at 14 hospital trusts in the Yorkshire and Humber region of the United Kingdom were invited to refer material from patients with newly diagnosed CRC aged 50 years or over between 1 April 2017 and 31 March 2019 for LS screening. Testing consisted of immunohistochemistry for MLH1, PMS2, MSH2 and MSH6 followed by BRAF mutation analysis ± MLH1 promoter methylation testing in cases showing MLH1 loss. A total of 3141 individual specimens were submitted for testing from 12 departments consisting of 3061 unique tumours and 2791 prospectively acquired patients with CRC. Defective mismatch repair (dMMR) was observed in 15% of cases. In cases showing MLH1 loss, 76% contained a detectable BRAF mutation and, of the remainder, 77% showed MLH1 promoter hypermethylation. Of the patients included in the final analysis, 81 (2.9%) had an indication for germline testing.ConclusionLS screening using the NICE diagnostics guidance pathway is deliverable at scale identifying significant numbers of patients with dMMR. This information is used to refer patients to regional clinical genetics services in addition to informing treatment pathways including the use of adjuvant/neoadjuvant chemotherapy and immunotherapy.

Original publication




Journal article



Publication Date





690 - 699


Pathology and Data Analytics, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK.


Yorkshire Cancer Research Bowel Cancer Improvement Programme Group, Humans, Colorectal Neoplasms, Colorectal Neoplasms, Hereditary Nonpolyposis, Genetic Predisposition to Disease, Proto-Oncogene Proteins B-raf, Immunohistochemistry, Prospective Studies, DNA Methylation, Mutation, Adult, Aged, Middle Aged, Female, Male, DNA Mismatch Repair, Early Detection of Cancer, Genetic Testing, Biomarkers, Tumor, United Kingdom, MutL Protein Homolog 1