Željko Antić1,2, Jiangyan Yu1,3, Beat C Bornhauser4, Stefan H Lelieveld1, Cedric G van der Ham1, Simon V van Reijmersdal1,3, Lionel Morgado1, Sarah Elitzur5, Jean-Pierre Bourquin4, Giovanni Cazzaniga6, Cornelia Eckert7, Mireia Camós8,9,10, Rosemary Sutton11, Hélène Cavé12,13, Anthony V Moorman14, Edwin Sonneveld1,15, Ad Geurts van Kessel3, Frank N van Leeuwen1, Peter M Hoogerbrugge1,15, Esmé Waanders1,16, Roland P Kuiper1,16. 1. Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands. 2. Department of Human Genetics, Hannover Medical School, Hannover, Germany. 3. Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands. 4. Department of Oncology and Children's Research Centre, University Children's Hospital Zurich, Zurich, Switzerland. 5. Pediatric Hematology-Oncology, Schneider Children's Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. 6. Centro Ricerca Tettamanti, Fondazione Tettamanti, University of Milan Bicocca, Monza, Italy. 7. Pediatric Oncology/Hematology, Charité - Universitätsmedizin Berlin, Berlin, Germany. 8. Leukemia and Other Pediatric Hemopathies, Developmental Tumor Biology Group, Institut de Recerca Sant Joan de Déu, Barcelona, Spain. 9. Hematology Laboratory, Hospital Sant Joan de Deu Barcelona, Barcelona, Spain. 10. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain. 11. Molecular Diagnostics, Children's Cancer Institute, University of New South Wales, Sydney, New South Wales, Australia. 12. Department of Genetics, Robert Debré Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France. 13. INSERM U1131, Saint-Louis Research Institute, University of Paris, Paris, France. 14. Wolfson Childhood Cancer Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK. 15. Dutch Childhood Oncology Group, Utrecht, The Netherlands. 16. Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
Abstract
INTRODUCTION: One-quarter of the relapses in children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) occur very early (within 18 months, before completion of treatment), and prognosis in these patients is worse compared to cases that relapse after treatment has ended. METHODS: In this study, we performed a genomic analysis of diagnosis-relapse pairs of 12 children who relapsed very early, followed by a deep-sequencing validation of all identified mutations. In addition, we included one case with a good initial treatment response and on-treatment relapse at the end of upfront therapy. RESULTS: We observed a dynamic clonal evolution in all cases, with relapse almost exclusively originating from a subclone at diagnosis. We identified several driver mutations that may have influenced the outgrowth of a minor clone at diagnosis to become the major clone at relapse. For example, a minimal residual disease (MRD)-based standard-risk patient with ETV6-RUNX1-positive leukemia developed a relapse from a TP53-mutated subclone after loss of the wildtype allele. Furthermore, two patients with TCF3-PBX1-positive leukemia that developed a very early relapse carried E1099K WHSC1 mutations at diagnosis, a hotspot mutation that was recurrently encountered in other very early TCF3-PBX1-positive leukemia relapses as well. In addition to alterations in known relapse drivers, we found two cases with truncating mutations in the cohesin gene RAD21. CONCLUSION: Comprehensive genomic characterization of diagnosis-relapse pairs shows that very early relapses in BCP-ALL frequently arise from minor subclones at diagnosis. A detailed understanding of the therapeutic pressure driving these events may aid the development of improved therapies.
INTRODUCTION: One-quarter of the relapses in children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) occur very early (within 18 months, before completion of treatment), and prognosis in these patients is worse compared to cases that relapse after treatment has ended. METHODS: In this study, we performed a genomic analysis of diagnosis-relapse pairs of 12 children who relapsed very early, followed by a deep-sequencing validation of all identified mutations. In addition, we included one case with a good initial treatment response and on-treatment relapse at the end of upfront therapy. RESULTS: We observed a dynamic clonal evolution in all cases, with relapse almost exclusively originating from a subclone at diagnosis. We identified several driver mutations that may have influenced the outgrowth of a minor clone at diagnosis to become the major clone at relapse. For example, a minimal residual disease (MRD)-based standard-risk patient with ETV6-RUNX1-positive leukemia developed a relapse from a TP53-mutated subclone after loss of the wildtype allele. Furthermore, two patients with TCF3-PBX1-positive leukemia that developed a very early relapse carried E1099K WHSC1 mutations at diagnosis, a hotspot mutation that was recurrently encountered in other very early TCF3-PBX1-positive leukemia relapses as well. In addition to alterations in known relapse drivers, we found two cases with truncating mutations in the cohesin gene RAD21. CONCLUSION: Comprehensive genomic characterization of diagnosis-relapse pairs shows that very early relapses in BCP-ALL frequently arise from minor subclones at diagnosis. A detailed understanding of the therapeutic pressure driving these events may aid the development of improved therapies.
Authors: Anne Schedel; Ulrike Anne Friedrich; Mina N F Morcos; Rabea Wagener; Juha Mehtonen; Titus Watrin; Claudia Saitta; Triantafyllia Brozou; Pia Michler; Carolin Walter; Asta Försti; Arka Baksi; Maria Menzel; Peter Horak; Nagarajan Paramasivam; Grazia Fazio; Robert J Autry; Stefan Fröhling; Meinolf Suttorp; Christoph Gertzen; Holger Gohlke; Sanil Bhatia; Karin Wadt; Kjeld Schmiegelow; Martin Dugas; Daniela Richter; Hanno Glimm; Merja Heinäniemi; Rolf Jessberger; Gianni Cazzaniga; Arndt Borkhardt; Julia Hauer; Franziska Auer Journal: Int J Mol Sci Date: 2022-05-05 Impact factor: 6.208