Lynch syndrome screening in colorectal cancer: results of a prospective 2‐year regional programme validating the NICE diagnostics guidance pathway throughout a 5.2‐million population

• Published in: Histopathology 2021-11, Vol.79 (5), p.690-699
• Main Authors: West, Nicholas P, Gallop, Niall, Kaye, Danny, Glover, Amy, Young, Caroline, Hutchins, Gordon G A, Brockmoeller, Scarlet F, Westwood, Alice C, Rossington, Hannah, Quirke, Philip
• Format: Article
• Language: English
• Subjects: Adult; Aged; Biomarkers, Tumor - genetics; Chemotherapy; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - diagnosis; Colorectal Neoplasms - genetics; Colorectal Neoplasms, Hereditary Nonpolyposis - diagnosis; Colorectal Neoplasms, Hereditary Nonpolyposis - genetics; DNA Methylation; DNA Mismatch Repair - genetics; Early Detection of Cancer - methods; Female; Genetic Predisposition to Disease; Genetic Testing - methods; Humans; Immunohistochemistry; Immunotherapy; Lynch syndrome; Male; Middle Aged; Mismatch repair; MLH1 protein; MSH2 protein; MSH6 protein; Mutation; MutL Protein Homolog 1 - genetics; Patients; Prospective Studies; Proto-Oncogene Proteins B-raf - genetics; Tumors; United Kingdom
• ISSN: 0309-0167; 1365-2559
• DOI: 10.1111/his.14390

Aims Screening 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 results Pathology 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. Conclusion LS 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.