Journal of clinical pathology · 2025
Multisite clinical cross-validation and variant interpretation of a next generation sequencing panel for lymphoid cancer prognostication.
СтатьяВалидационное исследованиеМногоцентровое исследованиеНазвание и аннотация: Перевод в очереди
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Sabatini Peter J B, Bridgers Josh, Huang Shujun, Downs Gregory, Zhang Tong, Sheen Clare, Park Nicole, Kridel Robert, Marra Marco A, Steidl Christian, Scott David W, Karsan Aly
Аннотация
AIMS: Genomic sequencing of lymphomas is under-represented in routine clinical testing despite having prognostic and predictive value. Clinical implementation is challenging due to a lack of consensus on reportable targets and a paucity of reference samples. We organised a cross-validation study of a lymphoma-tailored next-generation sequencing panel between two College of American Pathologists (CAP)-accredited clinical laboratories to mitigate these challenges.
METHODS: A consensus for the genomic targets was discussed between the two institutes based on recurrence in diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, chronic lymphocytic leukaemia and T-cell lymphomas. Using the same genomic targets, each laboratory ordered libraries independently and a cross-validation study was designed to exchange samples (8 cell lines and 22 clinical samples) and their FASTQ files.
RESULTS: The sensitivity of the panel when comparing different library preparation and bioinformatic workflows was between 97% and 99% and specificity was 100% when a 5% limit of detection cut-off was applied. To evaluate how the current standards for variant classification of tumours apply to lymphomas, the Association for Molecular Pathology/American Society of Clinical Oncology/CAP and OncoKB classification systems were applied to the panel. The majority of variants were assigned a possibly actionable class or likely pathogenic due to more limited evidence in the literature.
CONCLUSIONS: The cross-validation study highlights the benefits of sample and data exchange for clinical validation and provided a framework for reporting the findings in lymphoid malignancies.
METHODS: A consensus for the genomic targets was discussed between the two institutes based on recurrence in diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, chronic lymphocytic leukaemia and T-cell lymphomas. Using the same genomic targets, each laboratory ordered libraries independently and a cross-validation study was designed to exchange samples (8 cell lines and 22 clinical samples) and their FASTQ files.
RESULTS: The sensitivity of the panel when comparing different library preparation and bioinformatic workflows was between 97% and 99% and specificity was 100% when a 5% limit of detection cut-off was applied. To evaluate how the current standards for variant classification of tumours apply to lymphomas, the Association for Molecular Pathology/American Society of Clinical Oncology/CAP and OncoKB classification systems were applied to the panel. The majority of variants were assigned a possibly actionable class or likely pathogenic due to more limited evidence in the literature.
CONCLUSIONS: The cross-validation study highlights the benefits of sample and data exchange for clinical validation and provided a framework for reporting the findings in lymphoid malignancies.