Clonal dynamics in pediatric B-cell precursor acute lymphoblastic leukemia with very early relapse.
Por:
Antic Ž, Yu J, Bornhauser BC, Lelieveld SH, van der Ham CG, van Reijmersdal SV, Morgado L, Elitzur S, Bourquin JP, Cazzaniga G, Eckert C, Camós-Guijosa M, Sutton R, Cavé H, Moorman AV, Sonneveld E, Geurts van Kessel A, van Leeuwen FN, Hoogerbrugge PM, Waanders E and Kuiper RP
Publicada:
1 ene 2022
Ahead of Print:
1 oct 2021
Resumen:
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.
Filiaciones:
Antic Ž:
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
Department of Human Genetics, Hannover Medical School, Hannover, Germany
Yu J:
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
Bornhauser BC:
Department of Oncology and Children's Research Centre, University Children's Hospital Zurich, Zurich, Switzerland
Lelieveld SH:
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
van der Ham CG:
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
van Reijmersdal SV:
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
Morgado L:
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
Elitzur S:
Pediatric Hematology-Oncology, Schneider Children's Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Bourquin JP:
Department of Oncology and Children's Research Centre, University Children's Hospital Zurich, Zurich, Switzerland
Cazzaniga G:
Centro Ricerca Tettamanti, Fondazione Tettamanti, University of Milan Bicocca, Monza, Italy
Eckert C:
Pediatric Oncology/Hematology, Charité - Universitätsmedizin Berlin, Berlin, Germany
Camós-Guijosa M:
Leukemia and Other Pediatric Hemopathies, Developmental Tumor Biology Group, Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Hematology Laboratory, Hospital Sant Joan de Déu Barcelona, Barcelona, Spain
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
Sutton R:
Molecular Diagnostics, Children's Cancer Institute, University of New South Wales, Sydney, New South Wales, Australia
Cavé H:
Department of Genetics, Robert Debré Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
INSERM U1131, Saint-Louis Research Institute, University of Paris, Paris, France
Moorman AV:
Wolfson Childhood Cancer Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
Sonneveld E:
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
Dutch Childhood Oncology Group, Utrecht, The Netherlands
Geurts van Kessel A:
Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
van Leeuwen FN:
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
Hoogerbrugge PM:
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
Dutch Childhood Oncology Group, Utrecht, The Netherlands
Waanders E:
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
Kuiper RP:
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
hybrid, Green Published, Green Accepted
|