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

Wadensten, Elisabeth LU ; Wessman, Sandra ; Abel, Frida ; Diaz De Ståhl, Teresita ; Tesi, Bianca ; Orsmark Pietras, Christina LU ; Arvidsson, Linda ; Taylan, Fulya ; Fransson, Susanne and Vogt, Hartmut , et al. (2023) In JCO Precision Oncology 7. p.1-11
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... (More)

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.

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type
Contribution to journal
publication status
published
subject
keywords
Humans, Child, Precision Medicine, Neoplasm Recurrence, Local, Carcinoma, Gene Fusion, Genomics
in
JCO Precision Oncology
volume
7
article number
e2300039
pages
1 - 11
publisher
American Society of Clinical Oncology
external identifiers
  • pmid:37384868
  • scopus:85184586115
ISSN
2473-4284
DOI
10.1200/PO.23.00039
language
English
LU publication?
yes
id
3c3f0fab-65af-4070-95d2-9272c1546c3f
date added to LUP
2024-05-14 00:12:14
date last changed
2024-12-13 16:29:18
@article{3c3f0fab-65af-4070-95d2-9272c1546c3f,
  abstract     = {{<p>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.</p><p>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.</p><p>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<br>
 ALK mutations/fusions (n = 4), RAS/RAF/MEK/ERK pathway mutations (n = 14), <br>
 FGFR1 mutations/fusions (n = 5), <br>
 IDH1 mutations (n = 2), and <br>
 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%).<br>
 </p><p>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.</p>}},
  author       = {{Wadensten, Elisabeth and Wessman, Sandra and Abel, Frida and Diaz De Ståhl, Teresita and Tesi, Bianca and Orsmark Pietras, Christina and Arvidsson, Linda and Taylan, Fulya and Fransson, Susanne and Vogt, Hartmut and Poluha, Anna and Pradhananga, Sailendra and Hellberg, Maria and Lagerstedt-Robinson, Kristina and Raj Somarajan, Praveen and Samuelsson, Sofie and Orrsjö, Sara and Maqbool, Khurram and Henning, Karin and Strid, Tobias and Ek, Torben and Fagman, Henrik and Olsson Bontell, Thomas and Martinsson, Tommy and Puls, Florian and Kogner, Per and Wirta, Valtteri and Pronk, Cornelis Jan and Wille, Joakim and Rosenquist, Richard and Nistér, Monica and Mertens, Fredrik and Sabel, Magnus and Norén-Nyström, Ulrika and Grillner, Pernilla and Nordgren, Ann and Ljungman, Gustaf and Sandgren, Johanna and Gisselsson, David}},
  issn         = {{2473-4284}},
  keywords     = {{Humans; Child; Precision Medicine; Neoplasm Recurrence, Local; Carcinoma; Gene Fusion; Genomics}},
  language     = {{eng}},
  pages        = {{1--11}},
  publisher    = {{American Society of Clinical Oncology}},
  series       = {{JCO Precision Oncology}},
  title        = {{Diagnostic Yield From a Nationwide Implementation of Precision Medicine for all Children With Cancer}},
  url          = {{http://dx.doi.org/10.1200/PO.23.00039}},
  doi          = {{10.1200/PO.23.00039}},
  volume       = {{7}},
  year         = {{2023}},
}