Frontiers in Oncology (Aug 2023)
Feasibility to use whole-genome sequencing as a sole diagnostic method to detect genomic aberrations in pediatric B-cell acute lymphoblastic leukemia
- Fatemah Rezayee,
- Fatemah Rezayee,
- Jesper Eisfeldt,
- Jesper Eisfeldt,
- Aron Skaftason,
- Aron Skaftason,
- Ingegerd Öfverholm,
- Ingegerd Öfverholm,
- Shumaila Sayyab,
- Shumaila Sayyab,
- Ann Christine Syvänen,
- Ann Christine Syvänen,
- Khurram Maqbool,
- Henrik Lilljebjörn,
- Bertil Johansson,
- Bertil Johansson,
- Linda Olsson-Arvidsson,
- Linda Olsson-Arvidsson,
- Christina Orsmark Pietras,
- Anna Staffas,
- Anna Staffas,
- Lars Palmqvist,
- Lars Palmqvist,
- Thoas Fioretos,
- Thoas Fioretos,
- Thoas Fioretos,
- Lucia Cavelier,
- Lucia Cavelier,
- Linda Fogelstrand,
- Linda Fogelstrand,
- Jessica Nordlund,
- Jessica Nordlund,
- Valtteri Wirta,
- Valtteri Wirta,
- Richard Rosenquist,
- Richard Rosenquist,
- Richard Rosenquist,
- Gisela Barbany,
- Gisela Barbany
Affiliations
- Fatemah Rezayee
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Fatemah Rezayee
- Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
- Jesper Eisfeldt
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Jesper Eisfeldt
- Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
- Aron Skaftason
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Aron Skaftason
- Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden
- Ingegerd Öfverholm
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Ingegerd Öfverholm
- Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
- Shumaila Sayyab
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
- Shumaila Sayyab
- Science for Life Laboratory, Uppsala University, Uppsala, Sweden
- Ann Christine Syvänen
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
- Ann Christine Syvänen
- Science for Life Laboratory, Uppsala University, Uppsala, Sweden
- Khurram Maqbool
- Science for Life Laboratory, Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
- Henrik Lilljebjörn
- Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden
- Bertil Johansson
- Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden
- Bertil Johansson
- Department of Clinical Genetics, Pathology, and Molecular Diagnostics, Office for Medical Services, Region Skåne, Lund, Sweden
- Linda Olsson-Arvidsson
- Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden
- Linda Olsson-Arvidsson
- Department of Clinical Genetics, Pathology, and Molecular Diagnostics, Office for Medical Services, Region Skåne, Lund, Sweden
- Christina Orsmark Pietras
- Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden
- Anna Staffas
- Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden
- Anna Staffas
- 0Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Lars Palmqvist
- 1Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden
- Lars Palmqvist
- 2Department of Laboratory Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Thoas Fioretos
- Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden
- Thoas Fioretos
- Department of Clinical Genetics, Pathology, and Molecular Diagnostics, Office for Medical Services, Region Skåne, Lund, Sweden
- Thoas Fioretos
- 3Clinical Genomics Lund, Science for Life Laboratory, Lund University, Lund, Sweden
- Lucia Cavelier
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Lucia Cavelier
- Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
- Linda Fogelstrand
- 1Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden
- Linda Fogelstrand
- 2Department of Laboratory Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Jessica Nordlund
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
- Jessica Nordlund
- Science for Life Laboratory, Uppsala University, Uppsala, Sweden
- Valtteri Wirta
- 4Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Stockholm, Sweden
- Valtteri Wirta
- 5Genomic Medicine Center Karolinska, Karolinska University Hospital, Stockholm, Sweden
- Richard Rosenquist
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Richard Rosenquist
- Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
- Richard Rosenquist
- 5Genomic Medicine Center Karolinska, Karolinska University Hospital, Stockholm, Sweden
- Gisela Barbany
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Gisela Barbany
- Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
- DOI
- https://doi.org/10.3389/fonc.2023.1217712
- Journal volume & issue
-
Vol. 13
Abstract
IntroductionThe suitability of whole-genome sequencing (WGS) as the sole method to detect clinically relevant genomic aberrations in B-cell acute lymphoblastic leukemia (ALL) was investigated with the aim of replacing current diagnostic methods.MethodsFor this purpose, we assessed the analytical performance of 150 bp paired-end WGS (90x leukemia/30x germline). A set of 88 retrospective B-cell ALL samples were selected to represent established ALL subgroups as well as ALL lacking stratifying markers by standard-of-care (SoC), so-called B-other ALL.ResultsBoth the analysis of paired leukemia/germline (L/N)(n=64) as well as leukemia-only (L-only)(n=88) detected all types of aberrations mandatory in the current ALLTogether trial protocol, i.e., aneuploidies, structural variants, and focal copy-number aberrations. Moreover, comparison to SoC revealed 100% concordance and that all patients had been assigned to the correct genetic subgroup using both approaches. Notably, WGS could allocate 35 out of 39 B-other ALL samples to one of the emerging genetic subgroups considered in the most recent classifications of ALL. We further investigated the impact of high (90x; n=58) vs low (30x; n=30) coverage on the diagnostic yield and observed an equally perfect concordance with SoC; low coverage detected all relevant lesions.DiscussionThe filtration of the WGS findings with a short list of genes recurrently rearranged in ALL was instrumental to extract the clinically relevant information efficiently. Nonetheless, the detection of DUX4 rearrangements required an additional customized analysis, due to multiple copies of this gene embedded in the highly repetitive D4Z4 region. We conclude that the diagnostic performance of WGS as the standalone method was remarkable and allowed detection of all clinically relevant genomic events in the diagnostic setting of B-cell ALL.
Keywords
- B-cell acute lymphoblastic leukemia
- whole-genome sequencing
- genomic aberrations
- diagnostic validation
- class-defining genetic lesions
