Diagnostic yield and clinical impact of germline sequencing in children with CNS and extracranial solid tumors—a nationwide, prospective Swedish study
(2024) In The Lancet Regional Health - Europe 39.- Abstract
Background: Childhood cancer predisposition (ChiCaP) syndromes are increasingly recognized as contributing factors to childhood cancer development. Yet, due to variable availability of germline testing, many children with ChiCaP might go undetected today. We report results from the nationwide and prospective ChiCaP study that investigated diagnostic yield and clinical impact of integrating germline whole-genome sequencing (gWGS) with tumor sequencing and systematic phenotyping in children with solid tumors. Methods: gWGS was performed in 309 children at diagnosis of CNS (n = 123, 40%) or extracranial (n = 186, 60%) solid tumors and analyzed for disease-causing variants in 189 known cancer predisposing genes. Tumor sequencing data were... (More)
Background: Childhood cancer predisposition (ChiCaP) syndromes are increasingly recognized as contributing factors to childhood cancer development. Yet, due to variable availability of germline testing, many children with ChiCaP might go undetected today. We report results from the nationwide and prospective ChiCaP study that investigated diagnostic yield and clinical impact of integrating germline whole-genome sequencing (gWGS) with tumor sequencing and systematic phenotyping in children with solid tumors. Methods: gWGS was performed in 309 children at diagnosis of CNS (n = 123, 40%) or extracranial (n = 186, 60%) solid tumors and analyzed for disease-causing variants in 189 known cancer predisposing genes. Tumor sequencing data were available for 74% (227/309) of patients. In addition, a standardized clinical assessment for underlying predisposition was performed in 95% (293/309) of patients. Findings: The prevalence of ChiCaP diagnoses was 11% (35/309), of which 69% (24/35) were unknown at inclusion (diagnostic yield 8%, 24/298). A second-hit and/or relevant mutational signature was observed in 19/21 (90%) tumors with informative data. ChiCaP diagnoses were more prevalent among patients with retinoblastomas (50%, 6/12) and high-grade astrocytomas (37%, 6/16), and in those with non-cancer related features (23%, 20/88), and ≥2 positive ChiCaP criteria (28%, 22/79). ChiCaP diagnoses were autosomal dominant in 80% (28/35) of patients, yet confirmed de novo in 64% (18/28). The 35 ChiCaP findings resulted in tailored surveillance (86%, 30/35) and treatment recommendations (31%, 11/35). Interpretation: Overall, our results demonstrate that systematic phenotyping, combined with genomics-based diagnostics of ChiCaP in children with solid tumors is feasible in large-scale clinical practice and critically guides personalized care in a sizable proportion of patients. Funding: The study was supported by the Swedish Childhood Cancer Fund and the Ministry of Health and Social Affairs.
(Less)
- author
- organization
- publishing date
- 2024-04
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Childhood cancer predisposition, Germline variants, Somatic mutations, Whole-genome sequencing
- in
- The Lancet Regional Health - Europe
- volume
- 39
- article number
- 100881
- publisher
- Elsevier
- external identifiers
-
- scopus:85188909470
- ISSN
- 2666-7762
- DOI
- 10.1016/j.lanepe.2024.100881
- language
- English
- LU publication?
- yes
- id
- 0863266c-a3e8-44ca-90ef-54ab307dbf6a
- date added to LUP
- 2024-04-18 13:36:16
- date last changed
- 2024-04-18 13:37:09
@article{0863266c-a3e8-44ca-90ef-54ab307dbf6a,
abstract = {{<p>Background: Childhood cancer predisposition (ChiCaP) syndromes are increasingly recognized as contributing factors to childhood cancer development. Yet, due to variable availability of germline testing, many children with ChiCaP might go undetected today. We report results from the nationwide and prospective ChiCaP study that investigated diagnostic yield and clinical impact of integrating germline whole-genome sequencing (gWGS) with tumor sequencing and systematic phenotyping in children with solid tumors. Methods: gWGS was performed in 309 children at diagnosis of CNS (n = 123, 40%) or extracranial (n = 186, 60%) solid tumors and analyzed for disease-causing variants in 189 known cancer predisposing genes. Tumor sequencing data were available for 74% (227/309) of patients. In addition, a standardized clinical assessment for underlying predisposition was performed in 95% (293/309) of patients. Findings: The prevalence of ChiCaP diagnoses was 11% (35/309), of which 69% (24/35) were unknown at inclusion (diagnostic yield 8%, 24/298). A second-hit and/or relevant mutational signature was observed in 19/21 (90%) tumors with informative data. ChiCaP diagnoses were more prevalent among patients with retinoblastomas (50%, 6/12) and high-grade astrocytomas (37%, 6/16), and in those with non-cancer related features (23%, 20/88), and ≥2 positive ChiCaP criteria (28%, 22/79). ChiCaP diagnoses were autosomal dominant in 80% (28/35) of patients, yet confirmed de novo in 64% (18/28). The 35 ChiCaP findings resulted in tailored surveillance (86%, 30/35) and treatment recommendations (31%, 11/35). Interpretation: Overall, our results demonstrate that systematic phenotyping, combined with genomics-based diagnostics of ChiCaP in children with solid tumors is feasible in large-scale clinical practice and critically guides personalized care in a sizable proportion of patients. Funding: The study was supported by the Swedish Childhood Cancer Fund and the Ministry of Health and Social Affairs.</p>}},
author = {{Tesi, Bianca and Robinson, Kristina Lagerstedt and Abel, Frida and Díaz de Ståhl, Teresita and Orrsjö, Sara and Poluha, Anna and Hellberg, Maria and Wessman, Sandra and Samuelsson, Sofie and Frisk, Tony and Vogt, Hartmut and Henning, Karin and Sabel, Magnus and Ek, Torben and Pal, Niklas and Nyman, Per and Giraud, Geraldine and Wille, Joakim and Pronk, Cornelis Jan and Norén-Nyström, Ulrika and Borssén, Magnus and Fili, Maria and Stålhammar, Gustav and Herold, Nikolas and Tettamanti, Giorgio and Maya-Gonzalez, Carolina and Arvidsson, Linda and Rosén, Anna and Ekholm, Katja and Kuchinskaya, Ekaterina and Hallbeck, Anna Lotta and Nordling, Margareta and Palmebäck, Pia and Kogner, Per and Smoler, Gunilla Kanter and Lähteenmäki, Päivi and Fransson, Susanne and Martinsson, Tommy and Shamik, Alia and Mertens, Fredrik and Rosenquist, Richard and Wirta, Valtteri and Tham, Emma and Grillner, Pernilla and Sandgren, Johanna and Ljungman, Gustaf and Gisselsson, David and Taylan, Fulya and Nordgren, Ann}},
issn = {{2666-7762}},
keywords = {{Childhood cancer predisposition; Germline variants; Somatic mutations; Whole-genome sequencing}},
language = {{eng}},
publisher = {{Elsevier}},
series = {{The Lancet Regional Health - Europe}},
title = {{Diagnostic yield and clinical impact of germline sequencing in children with CNS and extracranial solid tumors—a nationwide, prospective Swedish study}},
url = {{http://dx.doi.org/10.1016/j.lanepe.2024.100881}},
doi = {{10.1016/j.lanepe.2024.100881}},
volume = {{39}},
year = {{2024}},
}