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  1. Article ; Online: Germline variant testing in serrated polyposis syndrome.

    Murphy, Aisling / Solomons, Joyce / Risby, Peter / Gabriel, Jessica / Bedenham, Tina / Johnson, Michael / Atkinson, Nathan / Bailey, Adam A / Bird-Lieberman, Elizabeth / Leedham, Simon J / East, James E / Biswas, Sujata

    Journal of gastroenterology and hepatology

    2022  Volume 37, Issue 5, Page(s) 861–869

    Abstract: Background and aim: Serrated polyposis syndrome (SPS) is now known to be the commonest polyposis syndrome. Previous analyses for germline variants have shown no consistent positive findings. To exclude other polyposis syndromes, 2019 British Society of ... ...

    Abstract Background and aim: Serrated polyposis syndrome (SPS) is now known to be the commonest polyposis syndrome. Previous analyses for germline variants have shown no consistent positive findings. To exclude other polyposis syndromes, 2019 British Society of Gastroenterology (BSG) guidelines advise gene panel testing if the patient is under 50 years, there are multiple affected individuals within a family, or there is dysplasia within any of the polyps.
    Methods: A database of SPS patients was established at the Oxford University Hospitals NHS Foundation Trust. Patients were referred for genetic assessment based on personal and family history and patient preference. The majority were tested for a hereditary colorectal cancer panel including MUTYH, APC, PTEN, SMAD4, BMPR1A, STK11, NTLH1, POLD1, POLE, GREM1 (40-kb duplication), PMS2, and Lynch syndrome mismatch repair genes.
    Results: One hundred and seventy-three patients were diagnosed with SPS based on World Health Organization 2019 criteria between February 2010 and December 2020. The mean age of diagnosis was 54.2 ± 16.8 years. Seventy-three patients underwent genetic testing and 15/73 (20.5%) were found to have germline variants, of which 7/73 (9.6%) had a pathogenic variant (MUTYH n = 2, SMAD4 n = 1, CHEK2 n = 2, POLD1 n = 1, and RNF43 n = 1). Only 60% (9/15) of these patients would have been recommended for gene panel testing according to current BSG guidelines.
    Conclusions: A total of 20.5% of SPS patients tested were affected by heterozygous germline variants, including previously unreported associations with CHEK2 and POLD1. This led to a change in management in seven patients (9.6%). Current recommendations may miss SPS associated with germline variants, which is more common than previously anticipated.
    MeSH term(s) Adenomatous Polyposis Coli/genetics ; Adult ; Aged ; Colorectal Neoplasms/diagnosis ; Colorectal Neoplasms, Hereditary Nonpolyposis/genetics ; Genetic Testing ; Germ Cells ; Germ-Line Mutation ; Humans ; Middle Aged ; Syndrome
    Language English
    Publishing date 2022-02-18
    Publishing country Australia
    Document type Journal Article
    ZDB-ID 632882-9
    ISSN 1440-1746 ; 0815-9319
    ISSN (online) 1440-1746
    ISSN 0815-9319
    DOI 10.1111/jgh.15791
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Recommendations for laboratory workflow that better support centralised amalgamation of genomic variant data: findings from CanVIG-UK national molecular laboratory survey.

    Allen, Sophie / Loong, Lucy / Garrett, Alice / Torr, Bethany / Durkie, Miranda / Drummond, James / Callaway, Alison / Robinson, Rachel / Burghel, George J / Hanson, Helen / Field, Joanne / McDevitt, Trudi / McVeigh, Terri P / Bedenham, Tina / Bowles, Christopher / Bradshaw, Kirsty / Brooks, Claire / Butler, Samantha / Del Rey Jimenez, Juan Carlos /
    Hawkes, Lorraine / Stinton, Victoria / MacMahon, Suzanne / Owens, Martina / Palmer-Smith, Sheila / Smith, Kenneth / Tellez, James / Valganon-Petrizan, Mikel / Waskiewicz, Erik / Yau, Michael / Eccles, Diana M / Tischkowitz, Marc / Goel, Shilpi / McRonald, Fiona / Antoniou, Antonis C / Morris, Eva / Hardy, Steven / Turnbull, Clare

    Journal of medical genetics

    2024  Volume 61, Issue 4, Page(s) 305–312

    Abstract: Background: National and international amalgamation of genomic data offers opportunity for research and audit, including analyses enabling improved classification of variants of uncertain significance. Review of individual-level data from National ... ...

    Abstract Background: National and international amalgamation of genomic data offers opportunity for research and audit, including analyses enabling improved classification of variants of uncertain significance. Review of individual-level data from National Health Service (NHS) testing of cancer susceptibility genes (2002-2023) submitted to the National Disease Registration Service revealed heterogeneity across participating laboratories regarding (1) the structure, quality and completeness of submitted data, and (2) the ease with which that data could be assembled locally for submission.
    Methods: In May 2023, we undertook a closed online survey of 51 clinical scientists who provided consensus responses representing all 17 of 17 NHS molecular genetic laboratories in England and Wales which undertake NHS diagnostic analyses of cancer susceptibility genes. The survey included 18 questions relating to 'next-generation sequencing workflow' (11), 'variant classification' (3) and 'phenotypical context' (4).
    Results: Widely differing processes were reported for transfer of variant data into their local LIMS (Laboratory Information Management System), for the formatting in which the variants are stored in the LIMS and which classes of variants are retained in the local LIMS. Differing local provisions and workflow for variant classifications were also reported, including the resources provided and the mechanisms by which classifications are stored.
    Conclusion: The survey responses illustrate heterogeneous laboratory workflow for preparation of genomic variant data from local LIMS for centralised submission. Workflow is often labour-intensive and inefficient, involving multiple manual steps which introduce opportunities for error. These survey findings and adoption of the concomitant recommendations may support improvement in laboratory dataflows, better facilitating submission of data for central amalgamation.
    MeSH term(s) Humans ; Workflow ; Laboratories ; State Medicine ; Genomics ; Neoplasms ; United Kingdom
    Language English
    Publishing date 2024-03-21
    Publishing country England
    Document type Journal Article
    ZDB-ID 220881-7
    ISSN 1468-6244 ; 0022-2593
    ISSN (online) 1468-6244
    ISSN 0022-2593
    DOI 10.1136/jmg-2023-109645
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Secondary (additional) findings from the 100,000 Genomes Project: Disease manifestation, health care outcomes, and costs of disclosure.

    Nolan, Joshua / Buchanan, James / Taylor, John / Almeida, Joao / Bedenham, Tina / Blair, Edward / Broadgate, Suzanne / Butler, Samantha / Cazeaux, Angela / Craft, Judith / Cranston, Treena / Crawford, Gillian / Forrest, Jamie / Gabriel, Jessica / George, Elaine / Gillen, Donna / Haeger, Ash / Hastings Ward, Jillian / Hawkes, Lara /
    Hodgkiss, Claire / Hoffman, Jonathan / Jones, Alan / Karpe, Fredrik / Kasperaviciute, Dalia / Kovacs, Erika / Leigh, Sarah / Limb, Elizabeth / Lloyd-Jani, Anjali / Lopez, Javier / Lucassen, Anneke / McFarlane, Carlos / O'Rourke, Anthony W / Pond, Emily / Sherman, Catherine / Stewart, Helen / Thomas, Ellen / Thomas, Simon / Thomas, Tessy / Thomson, Kate / Wakelin, Hannah / Walker, Susan / Watson, Melanie / Williams, Eleanor / Ormondroyd, Elizabeth

    Genetics in medicine : official journal of the American College of Medical Genetics

    2023  Volume 26, Issue 3, Page(s) 101051

    Abstract: Purpose: The UK 100,000 Genomes Project offered participants screening for additional findings (AFs) in genes associated with familial hypercholesterolemia (FH) or hereditary cancer syndromes including breast/ovarian cancer (HBOC), Lynch, familial ... ...

    Abstract Purpose: The UK 100,000 Genomes Project offered participants screening for additional findings (AFs) in genes associated with familial hypercholesterolemia (FH) or hereditary cancer syndromes including breast/ovarian cancer (HBOC), Lynch, familial adenomatous polyposis, MYH-associated polyposis, multiple endocrine neoplasia (MEN), and von Hippel-Lindau. Here, we report disclosure processes, manifestation of AF-related disease, outcomes, and costs.
    Methods: An observational study in an area representing one-fifth of England.
    Results: Data were collected from 89 adult AF recipients. At disclosure, among 57 recipients of a cancer-predisposition-associated AF and 32 recipients of an FH-associated AF, 35% and 88%, respectively, had personal and/or family history evidence of AF-related disease. During post-disclosure investigations, 4 cancer-AF recipients had evidence of disease, including 1 medullary thyroid cancer. Six women with an HBOC AF, 3 women with a Lynch syndrome AF, and 2 individuals with a MEN AF elected for risk-reducing surgery. New hyperlipidemia diagnoses were made in 6 FH-AF recipients and treatment (re-)initiated for 7 with prior hyperlipidemia. Generating and disclosing AFs in this region cost £1.4m; £8680 per clinically significant AF.
    Conclusion: Generation and disclosure of AFs identifies individuals with and without personal or familial evidence of disease and prompts appropriate clinical interventions. Results can inform policy toward secondary findings.
    MeSH term(s) Adult ; Humans ; Female ; Genetic Testing/methods ; Disclosure ; Neoplastic Syndromes, Hereditary/genetics ; Breast Neoplasms/genetics ; Hyperlipidemias/genetics ; Delivery of Health Care ; Genetic Predisposition to Disease
    Language English
    Publishing date 2023-12-19
    Publishing country United States
    Document type Observational Study ; Journal Article
    ZDB-ID 1455352-1
    ISSN 1530-0366 ; 1098-3600
    ISSN (online) 1530-0366
    ISSN 1098-3600
    DOI 10.1016/j.gim.2023.101051
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  4. Article ; Online: 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.

    Loong, Lucy / Huntley, Catherine / McRonald, Fiona / Santaniello, Francesco / Pethick, Joanna / Torr, Bethany / Allen, Sophie / Tulloch, Oliver / Goel, Shilpi / Shand, Brian / Rahman, Tameera / Luchtenborg, Margreet / Garrett, Alice / Barber, Richard / Bedenham, Tina / Bourn, David / Bradshaw, Kirsty / Brooks, Claire / Bruty, Jonathan /
    Burghel, George J / Butler, Samantha / Buxton, Chris / Callaway, Alison / Callaway, Jonathan / Drummond, James / Durkie, Miranda / Field, Joanne / Jenkins, Lucy / McVeigh, Terri P / Mountford, Roger / Nyanhete, Rodney / Petrides, Evgenia / Robinson, Rachel / Scott, Tracy / Stinton, Victoria / Tellez, James / Wallace, Andrew J / Yarram-Smith, Laura / Sahan, Kate / Hallowell, Nina / Eccles, Diana M / Pharoah, Paul / Tischkowitz, Marc / Antoniou, Antonis C / Evans, D Gareth / Lalloo, Fiona / Norbury, Gail / Morris, Eva / Burn, John / Hardy, Steven / Turnbull, Clare

    Journal of medical genetics

    2022  Volume 60, Issue 7, Page(s) 669–678

    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 ...

    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.
    MeSH term(s) Humans ; State Medicine ; DNA Mismatch Repair/genetics ; Laboratories ; Neoplasms ; Genomics
    Language English
    Publishing date 2022-12-26
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 220881-7
    ISSN 1468-6244 ; 0022-2593
    ISSN (online) 1468-6244
    ISSN 0022-2593
    DOI 10.1136/jmg-2022-108800
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  5. Article ; Online: A comparison of methods for EGFR mutation testing in non-small cell lung cancer.

    Young, Elizabeth C / Owens, Martina M / Adebiyi, Idowu / Bedenham, Tina / Butler, Rachel / Callaway, Jonathan / Cranston, Treena / Crosby, Charlene / Cree, Ian A / Dutton, Laura / Faulkes, Catherine / Faulkner, Claire / Howard, Emma / Knight, Julia / Huang, Yuanxue / Lavender, Louise / Lazarou, Lazarus P / Liu, Hongxiang / Mair, Debbie /
    Milano, Antonio / Sandell, Stacey / Skinner, Alison / Wallace, Andrew / Williams, Maggie / Spivey, Vicky / Goodall, John / Frampton, Jonathan / Ellard, Sian

    Diagnostic molecular pathology : the American journal of surgical pathology, part B

    2013  Volume 22, Issue 4, Page(s) 190–195

    Abstract: EGFR mutation testing of tumor samples is routinely performed to predict sensitivity to treatment with tyrosine kinase inhibitors for patients with non-small cell lung cancer. At least 9 different methodologies are employed in UK laboratories, and the ... ...

    Abstract EGFR mutation testing of tumor samples is routinely performed to predict sensitivity to treatment with tyrosine kinase inhibitors for patients with non-small cell lung cancer. At least 9 different methodologies are employed in UK laboratories, and the aim of this study was to compare the sensitivity of different methods for the detection of EGFR mutations. Participating laboratories were sent coded samples with varying mutation loads (from 0% to 15%) to be tested for the p.Leu858Arg (p.L858R) missense mutation and c.2235_2249del exon 19 deletion. The p.L858R mutation and deletions within exon 19 of the EGFR gene account for ∼90% of mutation-positive cases. The 11 laboratories used their standard testing method(s) and submitted 15 sets of results for the p.L858R samples and 10 for the exon 19 deletion. The p.Leu858Arg (p.L858R) mutation was detected at levels between 1% and 7.5% by Sanger sequencing, pyrosequencing, real-time polymerase chain reaction (PCR), amplification refractory mutation system, and capillary electrophoresis single-strand conformation analysis. The c.2235_2249del mutation was detected at 1% to 5% by fragment size analysis, Sanger sequencing or real-time PCR. A mutation was detected in 24/25 (96%) of the samples tested which contained 5% mutated DNA. The 1% sensitivity claimed for commercial real-time PCR-targeted EGFR tests was achieved and our results show greater sensitivity for the Sanger sequencing and pyrosequencing screening methods compared to the 10% to 20% detection levels cited on clinical diagnostic reports. We conclude that multiple methodologies are suitable for the detection of acquired EGFR mutations.
    MeSH term(s) Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/pathology ; Humans ; Mutation, Missense ; Pathology, Molecular/methods ; Receptor, Epidermal Growth Factor/genetics ; Sensitivity and Specificity ; Sequence Deletion ; United Kingdom
    Chemical Substances EGFR protein, human (EC 2.7.10.1) ; Receptor, Epidermal Growth Factor (EC 2.7.10.1)
    Language English
    Publishing date 2013-12
    Publishing country United States
    Document type Comparative Study ; Evaluation Studies ; Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't
    ZDB-ID 1098858-0
    ISSN 1533-4066 ; 1052-9551
    ISSN (online) 1533-4066
    ISSN 1052-9551
    DOI 10.1097/PDM.0b013e318294936c
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