Stratified Medicine Pediatrics: Cell-Free DNA and Serial Tumor Sequencing Identifies Subtype-Specific Cancer Evolution and Epigenetic States
Year: 2024
Type: article
Study design: Observational Study
Abstract: We profiled a large heterogeneous cohort of matched diagnostic relapse tumor tissue and paired plasma-derived cell-free DNA (cfDNA) from patients with relapsed and progressive solid tumors of childhood. Tissue and cfDNA sequencing results were concordant, with a wider spectrum of mutant alleles and higher degree of intratumor heterogeneity captured by the latter, if sufficient ctDNA was present. Serial tumor sequencing identified putative drivers of relapse, with alterations in epigenetic drivers being a common feature. In keeping with epigenetic alterations being a common driver of many childhood cancers, fragmentomic analysis of cfDNA identified tumor-specific epigenetic states and transcription factor binding sites accessible in chromatin. This study leverages a large and well-annotated genomic dataset of aggressive childhood malignancies, identifies genomic and epigenetic drivers of childhood cancer relapse, and highlights the power and practicality of cfDNA analysis to capture both intratumoral heterogeneity and the epigenetic state of cancer cells. Significance: In tumors of childhood, we identify mutations in epigenetic genes as drivers of relapse, with matched cfDNA sequencing showing significant intratumor genetic heterogeneity and cell-state specific patterns of chromatin accessibility. This highlights the power of cfDNA analysis to identify both genetic and epigenetic drivers of aggressive disease in pediatric cancers.
Source: Cancer Discovery
Authors: Sally L. George, Claire Lynn, Reda Stankunaite, Debbie Hughes, Carolin M. Sauer, Jane Chalker, Saira Waqar Ahmed, Minou Oostveen, Paula Z. Proszek, Lina Yuan, Ridwan Shaikh, Sabri Jamal, Ama Brew, Jennifer Tall, Tony Rogers, Steven C. Clifford, Josef Vormoor, Janet M. Shipley, Deborah A. Tweddle, Chris Jones, Courtney Willis, G.A. Amos Burke, Aditi Vedi, Lisa Howell, Robert Johnston, Helen Rees, Madeleine Adams, Angela Jesudason, Milind Ronghe, Martin Elliott, Emma Ross, Guy Makin, Quentin Campbell-Hewson, Richard G. Grundy, Jennifer Turnbull, Shaun Wilson, Victoria Lee, Juliet C. Gray, Sara Stoneham, Susanne A. Gatz, Lynley V. Marshall, Paola Angelini, John Anderson, George D. Cresswell, Trevor A. Graham, Bissan Al-Lazikani, Isidro Cortés-Ciriano, Pamela Kearns, J. Ciaran Hutchinson, Darren Hargrave, Thomas S. Jacques, Michael Hubank, Andrea Sottoriva, Louis Chesler
Institutions: Institute of Cancer Research, Royal Marsden Hospital, European Bioinformatics Institute, Great Ormond Street Hospital, Great Ormond Street Hospital for Children NHS Foundation Trust, Royal Marsden NHS Foundation Trust, Newcastle University, University Medical Center Utrecht, Princess Máxima Center, Royal Aberdeen Children's Hospital, Cambridge University Hospitals NHS Foundation Trust, University of Birmingham, Alder Hey Children's Hospital, Royal Belfast Hospital for Sick Children, Bristol Royal Hospital for Children, Noah's Ark Children's Hospital for Wales, Royal Hospital for Children, Royal Hospital for Sick Children, Leeds General Infirmary, Leicester Royal Infirmary, University of Manchester, Royal Manchester Children's Hospital, Great North Children's Hospital, Queen's Medical Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Trust, Sheffield Children's Hospital, Southampton General Hospital, University of Southampton, University College Hospital, University College London, Birmingham Children's Hospital, St. Anna Children's Cancer Research Institute, The University of Texas MD Anderson Cancer Center, Human Technopole
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: hybrid
Funders: American Institute for Cancer Research, AstraZeneca, Alexion Pharmaceuticals, Wellcome Trust, Higher Education Funding Council for England, Cancer Research UK, CHILDREN with CANCER UK, Associazione Italiana per la Ricerca sul Cancro, Genentech, Imperial Experimental Cancer Medicine Centre, H2020 Marie Skłodowska-Curie Actions, HORIZON EUROPE Marie Sklodowska-Curie Actions
Awards: G1913124430, G1947269863, G2019728789, Nanopore sequencing of cell-free DNA for the sensitive detection, molecular profiling and monitoring of childhood cancers, G2781764237, Evolutionary Predictions In Colorectal Cancer (EPICC), Evolutionary Predictions In Colorectal Cancer (EPICC), G5357172207, G6692431212, G6775184743, G6958774849
OpenAlex ID: W4405522877