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Lookup NU author(s): Professor Sir John BurnORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2024 The Author(s). Background: Lynch Syndrome (LS) is a cancer predisposition syndrome caused by constitutional pathogenic variants in the mismatch repair (MMR) genes. To date, fragmentation of clinical and genomic data has restricted understanding of national LS ascertainment and outcomes, and precluded evaluation of NICE guidance on testing and management. To address this, via collaboration between researchers, the National Disease Registration Service (NDRS), NHS Genomic Medicine Service Alliances (GMSAs), and NHS Regional Clinical Genetics Services, a comprehensive registry of LS carriers in England has been established. Methods: For comprehensive ascertainment of retrospectively identified MMR pathogenic variant (PV) carriers (diagnosed prior to January 1, 2023), information was retrieved from all clinical genetics services across England, then restructured, amalgamated, and validated via a team of trained experts in NDRS. An online submission portal was established for prospective ascertainment from January 1, 2023. The resulting data, stored in a secure database in NDRS, were used to investigate the demographic and genetic characteristics of the cohort, censored at July 25, 2023. Cancer outcomes were investigated via linkage to the National Cancer Registration Dataset (NCRD). Findings: A total of 11,722 retrospective and 570 prospective data submissions were received, resulting in a comprehensive English National Lynch Syndrome Registry (ENLSR) comprising 9030 unique individuals. The most frequently identified pathogenic MMR genes were MSH2 and MLH1 at 37.2% (n = 3362) and 29.1% (n = 2624), respectively. 35.9% (n = 3239) of the ENLSR cohort received their LS diagnosis before their first cancer diagnosis (presumptive predictive germline test). Of these, 6.3% (n = 204) developed colorectal cancer, at a median age of initial diagnosis of 51 (IQR 40–62), compared to 73 years (IQR 64–80) in the general population (p < 0.0001). Interpretation: The ENLSR represents the first comprehensive national registry of PV carriers in England and one of the largest cohorts of MMR PV carriers worldwide. The establishment of a secure, centralised infrastructure and mechanism for routine registration of newly identified carriers ensures sustainability of the data resource. Funding: This work was funded by the Wellcome Trust, Cancer Research UK and Bowel Cancer UK. The funder of this study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
Author(s): Huntley C, Loong L, Mallinson C, Bethell R, Rahman T, Alhaddad N, Tulloch O, Zhou X, Lee J, Eves P, Cook J, Armstrong R, Ahmed M, McVeigh T, DeSouza B, Kulkarni A, Bezuidenhout H, Martin R, Holliday D, Hart R, Lalloo F, Donaldson A, Cleaver R, Willis C, Kiesel V, O'Reilly M-A, Halliday D, Solomons J, Ong KR, McRonald F, Torr B, Burn J, Shaw A, Morris EJA, Monahan K, Hardy S, Turnbull C
Publication type: Article
Publication status: Published
Journal: eClinicalMedicine
Year: 2024
Volume: 69
Print publication date: 01/03/2024
Online publication date: 07/02/2024
Acceptance date: 17/01/2024
Date deposited: 20/02/2024
ISSN (electronic): 2589-5370
Publisher: Elsevier Ltd
URL: https://doi.org/10.1016/j.eclinm.2024.102465
DOI: 10.1016/j.eclinm.2024.102465
Data Access Statement: Summary data relevant to the study are included in the article or supplementary information. Individual-level data used in this study are held within NDRS under robust privacy, security and confidentiality procedures and only available to properly authorised analysts and researchers under access arrangements through the NDRS Data Access and Release Service.
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