Diagnostic Yield From a Nationwide Implementation of Precision Medicine for all Children With Cancer

JCO Precision Oncology · 39 authors, 27 centres

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TL;DR

This prospective nationwide cohort study implemented whole-genome sequencing for 117 children with solid cancers in Sweden. The sequencing provided clinically relevant genomic data in the majority of patients, contributing to subclassification in 50% and identifying potential treatment targets in 26%.

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The study implemented prospective whole-genome sequencing (WGS) of tumor and germline DNA, with complementary RNA-Seq in some cases, for all children diagnosed with a primary or relapsed solid malignancy in Sweden over 14 months. Of 118 tumors analyzed from 117 patients, somatic mutations were found in 112, with 106 (95%) showing alterations with clear clinical correlation. In 59 cases (50%), sequencing contributed to additional subclassification or detection of prognostic markers. Potential treatment targets were identified in 31 patients (26%), and clinically relevant germline variants were found in 8 of 94 patients (8.5%). A limitation was that only 57% of estimated eligible patients were included, and fresh tissue requirements excluded 21% of enrolled patients. The study demonstrates the diagnostic value of large-scale genomic profiling in an unselected pediatric cancer cohort, though the early phase precludes survival analysis.

STUDY TYPE

cohort

SPECIALTY

pediatrics

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ORIGINAL PAPER

PMC10581599

Diagnostic Yield From a Nationwide Implementation of Precision Medicine for all Children With Cancer

JCO Precision Oncology

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ABSTRACT

Abstract PURPOSE Several studies have indicated that broad genomic characterization of childhood cancer provides diagnostically and/or therapeutically relevant information in selected high-risk cases. However, the extent to which such characterization offers clinically actionable data in a prospective broadly inclusive setting remains largely unexplored. METHODS We implemented prospective whole-genome sequencing (WGS) of tumor and germline, complemented by whole-transcriptome sequencing (RNA-Seq) for all children diagnosed with a primary or relapsed solid malignancy in Sweden. Multidisciplinary molecular tumor boards were set up to integrate genomic data in the clinical decision process along with a medicolegal framework enabling secondary use of sequencing data for research purposes. RESULTS During the study's first 14 months, 118 solid tumors from 117 patients were subjected to WGS, with complementary RNA-Seq for fusion gene detection in 52 tumors. There was no significant geographic bias in patient enrollment, and the included tumor types reflected the annual national incidence of pediatric solid tumor types. Of the 112 tumors with somatic mutations, 106 (95%) exhibited alterations with a clear clinical correlation. In 46 of 118 tumors (39%), sequencing only corroborated histopathological diagnoses, while in 59 cases (50%), it contributed to additional subclassification or detection of prognostic markers. Potential treatment targets were found in 31 patients (26%), most commonly ALK mutations/fusions (n = 4), RAS/RAF/MEK/ERK pathway mutations (n = 14), FGFR1 mutations/fusions (n = 5), IDH1 mutations (n = 2), and NTRK2 gene fusions (n = 2). In one patient, the tumor diagnosis was revised based on sequencing. Clinically relevant germline variants were detected in 8 of 94 patients (8.5%). CONCLUSION Up-front, large-scale genomic characterization of pediatric solid malignancies provides diagnostically valuable data in the majority of patients also in a largely unselected cohort.

CITATION EXPORT

Elisabeth Wadensten, Sandra Wessman, Frida Abel et al.. Diagnostic Yield From a Nationwide Implementation of Precision Medicine for all Children With Cancer. JCO Precision Oncology. (2023). https://doi.org/10.1200/PO.23.00039

AUTHORS

39 · 27 CENTRES

Elisabeth Wadensten, Sandra Wessman, Frida Abel, Teresita Diaz De Ståhl, Bianca Tesi, Christina Orsmark Pietras, Linda Arvidsson, Fulya Taylan, Susanne Fransson, Hartmut Vogt, Anna Poluha, Sailendra Pradhananga, Maria Hellberg, Kristina Lagerstedt-Robinson, Praveen Raj Somarajan, Sofie Samuelsson, Sara Orrsjö, Khurram Maqbool, Karin Henning, Tobias Strid, Torben Ek, Henrik Fagman, Thomas Olsson Bontell, Tommy Martinsson, Florian Puls, Per Kogner, Valtteri Wirta, Cornelis Jan Pronk, Joakim Wille, Richard Rosenquist, Monica Nistér, Fredrik Mertens, Magnus Sabel, Ulrika Norén-Nyström, Pernilla Grillner, Ann Nordgren, Gustaf Ljungman, Johanna Sandgren, David Gisselsson

1Section of Clinical Genetics, Pathology and Molecular Diagnostics, Medical Services, Region Skåne, University Hospital, SE-22185, Lund, Sweden
2Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, BMC C13, SE-221 84, Lund, Sweden
3Clinical Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, Sweden
4Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
5Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden
6Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
7Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
8Clinical Genetics, Karolinska University Hospital, Solna, Sweden
9Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden
10Crown Princess Victoria's Child and Youth Hospital in Linköping, and Division of Children's and Women's Health, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
11Clinical Genetics, Uppsala University Hospital, Uppsala, Sweden
12Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
13Department of Microbiology, Tumor and Cell Biology, Clinical Genomics Stockholm, Science Life Laboratory, Karolinska Institutet, Solna, Sweden
14Section for Pediatric Hematology and Oncology, Karolinska University Hospital, Stockholm, Sweden
15Childhood Cancer Research Unit, Department for Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
16Department of Clinical Pathology and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
17Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg
18Queen Silvia Children's Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden
19Department of Clinical Pathology, Sahlgrenska University Hospital, Gothenburg, Sweden
20Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
21Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden
22Genomic Medicine Center Karolinska, Karolinska University Hospital, Stockholm, Sweden
23School of Engineering Sciences in Chemistry, Biotechnology and Health, Clinical Genomics Stockholm, Science Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden
24Childhood Cancer Centre, Skåne University Hospital, Lund, Sweden
25Department of Clinical Sciences, Pediatrics, Umeå University, Umeå, Sweden
26Department of Women's and Children's Health, Uppsala University, Sweden
27Department of Pediatric Oncology, Uppsala University Children's Hospital, 751 35 Uppsala, Sweden