Germline mismatch repair (MMR) gene analyses from English NHS regional molecular genomics laboratories 1996-2020: development of a national resource of patient-level genomics laboratory records

doi:10.1136/jmg-2022-108800

. 2022 Dec 26;jmg-2022-108800.

doi: 10.1136/jmg-2022-108800. Online ahead of print.

Germline mismatch repair (MMR) gene analyses from English NHS regional molecular genomics laboratories 1996-2020: development of a national resource of patient-level genomics laboratory records

Lucy Loong^#¹, Catherine Huntley^#¹, Fiona McRonald^#², Francesco Santaniello^#^{2

3}, Joanna Pethick², Bethany Torr¹, Sophie Allen¹, Oliver Tulloch^{2

3}, Shilpi Goel^{2

3}, Brian Shand^{2

3}, Tameera Rahman^{2

3}, Margreet Luchtenborg^{2

4}, Alice Garrett¹, Richard Barber⁵, Tina Bedenham⁶, David Bourn⁷, Kirsty Bradshaw⁸, Claire Brooks⁹, Jonathan Bruty¹⁰, George J Burghel¹¹, Samantha Butler⁵, Chris Buxton¹², Alison Callaway¹³, Jonathan Callaway¹³, James Drummond¹⁰, Miranda Durkie¹⁴, Joanne Field⁸, Lucy Jenkins⁹, Terri P McVeigh^{1

15}, Roger Mountford¹⁶, Rodney Nyanhete¹⁴, Evgenia Petrides⁶, Rachel Robinson¹⁷, Tracy Scott¹⁷, Victoria Stinton¹⁶, James Tellez⁷, Andrew J Wallace¹¹, Laura Yarram-Smith¹², Kate Sahan¹⁸, Nina Hallowell¹⁸, Diana M Eccles^{19

20}, Paul Pharoah²¹, Marc Tischkowitz²¹, Antonis C Antoniou²¹, D Gareth Evans^{11

22}, Fiona Lalloo¹¹, Gail Norbury²³, Eva Morris²⁴, John Burn^#²⁵, Steven Hardy^#², Clare Turnbull^#^{26

15}

Affiliations

¹ Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, UK.
² NHS Digital, National Disease Registration Service, London, UK.
³ Health Data Insight CIC, Cambridge, UK.
⁴ Centre for Cancer, Society & Public Health, King's College London, London, UK.
⁵ Central and South Genomic Laboratory Hub, West Midlands Regional Genetics Laboratory, Birmingham, UK.
⁶ West Midlands, Oxford and Wessex Genomic Laboratory Hub, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
⁷ North East and Yorkshire Genomic Laboratory Hub, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK.
⁸ East Midlands and East of England Genomics Laboratory, Nottingham University Hospitals NHS Trust, Nottingham, UK.
⁹ North Thames Genomic Laboratory Hub, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
¹⁰ East Genomic Laboratory Hub, Cambridge University Hospitals Genomic Laboratory, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
¹¹ Manchester Centre for Genomic Medicine and North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust, Manchester, UK.
¹² Bristol Genetics Laboratory, Southmead Hospital, Bristol, UK.
¹³ Wessex Regional Genetics Laboratory, Salisbury Hospital NHS Foundation Trust, Salisbury, UK.
¹⁴ Sheffield Diagnostic Genetics Service, North East and Yorkshire Genomic Laboratory Hub, Sheffield Children's NHS Foundation Trust, Sheffield, UK.
¹⁵ Cancer Genetics Unit, Royal Marsden Hospital NHS Trust, London, UK.
¹⁶ North West Genomic Laboratory Hub (Liverpool), Manchester Centre for Genomic Medicine, Liverpool, UK.
¹⁷ Yorkshire and North East Genomic Laboratory Hub, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
¹⁸ The Ethox Centre and Wellcome Centre for Ethics and Humanities, Nuffield Department of Population Health, University of Oxford Ethox Centre, Oxford, UK.
¹⁹ Cancer Sciences, University of Southampton Faculty of Medicine, Southampton, UK.
²⁰ Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK.
²¹ Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge, UK.
²² Division of Evolution & Genomic Sciences, The University of Manchester, Manchester, UK.
²³ South East Genomic Laboratory Hub, Guy's and St Thomas' Hospitals NHS Trust, London, UK.
²⁴ Nuffield Department of Population Health, University of Oxford, Oxford, UK.
²⁵ Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
²⁶ Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, UK clare.turnbull@icr.ac.uk.

^# Contributed equally.

PMID: 36572524
DOI: 10.1136/jmg-2022-108800

Germline mismatch repair (MMR) gene analyses from English NHS regional molecular genomics laboratories 1996-2020: development of a national resource of patient-level genomics laboratory records

Lucy Loong et al. J Med Genet. 2022.

. 2022 Dec 26;jmg-2022-108800.

doi: 10.1136/jmg-2022-108800. Online ahead of print.

Authors

Affiliations

¹ Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, UK.
² NHS Digital, National Disease Registration Service, London, UK.
³ Health Data Insight CIC, Cambridge, UK.
⁴ Centre for Cancer, Society & Public Health, King's College London, London, UK.
⁵ Central and South Genomic Laboratory Hub, West Midlands Regional Genetics Laboratory, Birmingham, UK.
⁶ West Midlands, Oxford and Wessex Genomic Laboratory Hub, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
⁷ North East and Yorkshire Genomic Laboratory Hub, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK.
⁸ East Midlands and East of England Genomics Laboratory, Nottingham University Hospitals NHS Trust, Nottingham, UK.
⁹ North Thames Genomic Laboratory Hub, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
¹⁰ East Genomic Laboratory Hub, Cambridge University Hospitals Genomic Laboratory, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
¹¹ Manchester Centre for Genomic Medicine and North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust, Manchester, UK.
¹² Bristol Genetics Laboratory, Southmead Hospital, Bristol, UK.
¹³ Wessex Regional Genetics Laboratory, Salisbury Hospital NHS Foundation Trust, Salisbury, UK.
¹⁴ Sheffield Diagnostic Genetics Service, North East and Yorkshire Genomic Laboratory Hub, Sheffield Children's NHS Foundation Trust, Sheffield, UK.
¹⁵ Cancer Genetics Unit, Royal Marsden Hospital NHS Trust, London, UK.
¹⁶ North West Genomic Laboratory Hub (Liverpool), Manchester Centre for Genomic Medicine, Liverpool, UK.
¹⁷ Yorkshire and North East Genomic Laboratory Hub, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
¹⁸ The Ethox Centre and Wellcome Centre for Ethics and Humanities, Nuffield Department of Population Health, University of Oxford Ethox Centre, Oxford, UK.
¹⁹ Cancer Sciences, University of Southampton Faculty of Medicine, Southampton, UK.
²⁰ Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK.
²¹ Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge, UK.
²² Division of Evolution & Genomic Sciences, The University of Manchester, Manchester, UK.
²³ South East Genomic Laboratory Hub, Guy's and St Thomas' Hospitals NHS Trust, London, UK.
²⁴ Nuffield Department of Population Health, University of Oxford, Oxford, UK.
²⁵ Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
²⁶ Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, UK clare.turnbull@icr.ac.uk.

^# Contributed equally.

PMID: 36572524
DOI: 10.1136/jmg-2022-108800

Abstract

Objective: To describe national patterns of National Health Service (NHS) analysis of mismatch repair (MMR) genes in England using individual-level data submitted to the National Disease Registration Service (NDRS) by the NHS regional molecular genetics laboratories.

Design: Laboratories submitted individual-level patient data to NDRS against a prescribed data model, including (1) patient identifiers, (2) test episode data, (3) per-gene results and (4) detected sequence variants. Individualised per-laboratory algorithms were designed and applied in NDRS to extract and map the data to the common data model. Laboratory-level MMR activity audit data from the Clinical Molecular Genetics Society/Association of Clinical Genomic Science were used to assess early years' missing data.

Results: Individual-level data from patients undergoing NHS MMR germline genetic testing were submitted from all 13 English laboratories performing MMR analyses, comprising in total 16 722 patients (9649 full-gene, 7073 targeted), with the earliest submission from 2000. The NDRS dataset is estimated to comprise >60% of NHS MMR analyses performed since inception of NHS MMR analysis, with complete national data for full-gene analyses for 2016 onwards. Out of 9649 full-gene tests, 2724 had an abnormal result, approximately 70% of which were (likely) pathogenic. Data linkage to the National Cancer Registry demonstrated colorectal cancer was the most frequent cancer type in which full-gene analysis was performed.

Conclusion: The NDRS MMR dataset is a unique national pan-laboratory amalgamation of individual-level clinical and genomic patient data with pseudonymised identifiers enabling linkage to other national datasets. This growing resource will enable longitudinal research and can form the basis of a live national genomic disease registry.

Keywords: Databases, Genetic; Genetic Testing; Genetics, Medical; Genetics, Population; Genomics.

Conflict of interest statement

Competing interests: TPM has received grants in the last 36 months from Roche, Novartis and Hermitage Medical Group for support in educational materials, from MSD/Merck/AstraZeneca, Novartis, Iheed and RCPI for consultation as a subject matter expert, and has taken part in advisory boards for Roche, UK CGG (unpaid), Breast Cancer Now (unpaid), and Ovacare (unpaid). NH declares stock in GSK and AstraZeneca. FL has sat as an Expert Advisor for the NHSE&I Lynch Syndrome task and finish group. DE is chair of the Medical Research Council Clinical Academic Research partnership funding committee, and recipient of the Assessor Research Council of Norway Centres of Excellence Funding awards. CT has received honoraria for educational activities and advisory boards from AstraZeneca and Roche (all proceeds donated to registered charity 11511580).