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. 2023 Jul;60(7):669-678.
doi: 10.1136/jmg-2022-108800. Epub 2022 Dec 26.

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 Pethick  2 , Bethany Torr  1 , Sophie Allen  1 , Oliver Tulloch  2   3 , Shilpi Goel  2   3 , Brian Shand  2   3 , Tameera Rahman  2   3 , Margreet Luchtenborg  2   4 , Alice Garrett  1 , Richard Barber  5 , Tina Bedenham  6 , David Bourn  7 , Kirsty Bradshaw  8 , Claire Brooks  9 , Jonathan Bruty  10 , George J Burghel  11 , Samantha Butler  5 , Chris Buxton  12 , Alison Callaway  13 , Jonathan Callaway  13 , James Drummond  10 , Miranda Durkie  14 , Joanne Field  8 , Lucy Jenkins  9 , Terri P McVeigh  1   15 , Roger Mountford  16 , Rodney Nyanhete  14 , Evgenia Petrides  6 , Rachel Robinson  17 , Tracy Scott  17 , Victoria Stinton  16 , James Tellez  7 , Andrew J Wallace  11 , Laura Yarram-Smith  12 , Kate Sahan  18 , Nina Hallowell  18 , Diana M Eccles  19   20 , Paul Pharoah  21 , Marc Tischkowitz  21 , Antonis C Antoniou  21 , D Gareth Evans  11   22 , Fiona Lalloo  11 , Gail Norbury  23 , Eva Morris  24 , John Burn #  25 , Steven Hardy #  2 , Clare Turnbull #  26   15
Affiliations

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. 2023 Jul.

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.

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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).

Figures

Figure 1
Figure 1
Schematic showing encryption of NHS numbers to form pseudo-ID1 and dates of birth and postcode combinations into pseudo-ID2 at the point of upload for patient-level records in the laboratory data extracts. The pseudo-IDs are recreated from NHS numbers, dates of birth and postcodes held in the cancer registry to facilitate linkage of records. API, application programming interface; MMR, mismatch repair; NHS, National Health Service.
Figure 2
Figure 2
NDRS germline MMR dataset comparison with estimated total NHS germline MMR gene analyses in England for financial years April 1996–March 2020. Y-axis: number of patients who received an NHS MMR analysis. X-axis: financial year (fy). Blue bars: NDRS total tests−total number of patients who received an NHS MMR analysis captured in the NDRS germline MMR dataset. Orange bars: Adjusted consensus analyses total−estimate of the national total NHS MMR analyses undertaken, calculated from integration of NDRS and CMGS/ACGS audit data. The table beneath the X-axis shows the NDRS germline MMR dataset and adjusted consensus analyses totals broken down into full gene and targeted analyses. (See online supplemental methods and online supplemental table 2 for calculation.) Both NDRS and CMGS/ACGS data included a small number of repeat MMR analyses for patients returning to clinical genetics services and receiving subsequent MMR gene analyses. Patients in the NDRS germline MMR dataset with >1 test episode=439 (see online supplemental methods). CMGS/ACGS, Clinical Molecular Genetics Society/Association of Clinical Genomic Science; MMR, mismatch repair; NDRS, National Disease Registration Service; NHS, National Health Service.
Figure 3
Figure 3
Combinations of MMR genes analysed together over time in the NDRS germline MMR dataset 2001–2019. Only full-gene analyses in patients’ first test episodes are included to represent the testing patients received on their first contact with a clinical genetics service in a given year. X-axis: calendar years. Y-axis: proportion of patients in a given calendar year receiving each combination of gene analyses. MMR, mismatch repair; NDRS, National Disease Registration Service.
Figure 4
Figure 4
Cancer registrations linked to the NDRS germline MMR dataset. X-axis: cancer site; Y-axis: number of unique cancers registered in the NDRS national cancer registry diagnosed between 1995 and 2019 inclusive (multiple primaries, multiple cancer sites and cancers diagnosed before and after a genetic test in a single patient have all been included). Turquoise: cancers diagnosed before the genetic test report date. Orange: cancers diagnosed after the genetic test report date (for patients with multiple test episodes, this is relative to the first test episode for that patient). Plot separated into cancers linked to full-gene MMR analyses (left) and targeted MMR analyses (right). MMR, mismatch repair; NDRS, National Disease Registration Service.
Figure 5
Figure 5
Result breakdown and availability of pathogenicity classification for full-gene germline MMR analyses by year. For patients found to have multiple variants potentially in multiple genes, only the most significant result (P>LP>VUS>abnormal unclassified>normal) for that patient test episode is counted. For the small number of patients with multiple full-gene test episodes in different years, the result of each test episode is represented in the respective year. Abnormal unclassified refers to results labelled by the submitting laboratory as abnormal but for which no pathogenicity classification was available. X-axis: calendar years; Y-axis: proportion of patients tested that year; Table: percentage of patients tested that year with a given result outcome. MMR, mismatch repair; LP, likely pathogenic; P, pathogenic; VUS, variant of uncertain significance.
See this image and copyright information in PMC

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