Dr Christopher Trethewey
Position: Clinical Research Associate
Personal home page: https://pubmed.ncbi.nlm.nih.gov/?term=Trethewey+CS
PubMed journal articles - click here
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Molecular profiling of circulating tumour DNA in aggressive lymphoid malignancies
Circulating tumour DNA (ctDNA) can be used to profile, detect, and monitor cancers. Technical advances in next-generation sequencing (NGS) strategies to address limitations in ctDNA detection and the precise classification of lymphoid cancers, using mutational features and bioinformatics tools, may help diagnosis and have predictive value for treatment. Despite these advances, application of ctDNA in current clinical practice is absent, with translational studies yet to be carried out in the U.K. for patient stratification. This study describes the development of an effective NGS workflow, comprising design of a pan-lymphoma, targeted panel focusing upon molecular characteristics specific to B-cell and T-cell malignancies for profiling ctDNA, coupled with custom bioinformatic workflow 'Deep-sequencing and Evaluation of Lymphoid Variant Effects' (DELVE). DELVE enables detection of aberrant somatic hyper-mutation (aSHM) sites including immunoglobulin heavy chain locus (IGH), fusions and clonal immunoglobulin repertoire detection. Clinical utility of ctDNA and mutational profiling by pan-lymphoma targeted panel/DELVE were investigated in Diffuse Large B-cell Lymphoma (DLBCL), primary cutaneous diffuse large B-cell lymphoma (PCDLBCL-LT) and peripheral T-cell lymphoma (PTCL). A DLBCL discovery cohort of six patients comparing FFPE and baseline ctDNA was followed by a validation cohort and longitudinal analysis during treatment. 14/15 DLBCL exhibited detectable ctDNA at baseline. Sequencing of tissue and plasma revealed significant aSHM, with detectable HMRN and LymphGen classifications. In a case of PCDLBCL-LT, limitations in use of ctDNA to monitor treatment response were evidenced with no detectable ctDNA throughout clinical course, including following 2 systemic relapses and ctDNA was detectable only when the patient was treated with BTKi. Finally, in PTCL (n=6), proof of principle and comparison with Ion Torrent sequencing was performed. This work demonstrated the feasibility of using a pan-lymphoma targeted panel and the DELVE pipeline to profile tumours and monitor residual disease and set the basis for larger scale studies.
2023, Blood Advances. DOI: 10.1182/bloodadvances.2022009366
Ross A Jackson, Robert Graham Britton, Sandrine Jayne, Susann Lehmann, Caroline M Cowley, Christopher Simon Trethewey, Victoria M Smith, Ralf Schmid, Christopher Fegan, Harriet Sarah Walter, Martin JS Dyer
Limitations of Monitoring Disease Progression Using Circulating Tumor DNA in Lymphoma: An Example From Primary Cutaneous DLBCL Leg-type.
Multiple mutations at exon 2 of RHOA detected in plasma from patients with peripheral T-cell lymphoma.
Blood Adv. 2020
Successful Treatment of Primary Cutaneous Diffuse Large B-Cell Lymphoma Leg Type With Single-Agent Venetoclax.
2019, JCO Precision Oncology.DOI: 10.1200/PO.19.00002