Diagnostic yield and clinical impact of germline sequencing in children with CNS and extracranial solid tumors-a nationwide, prospective Swedish study.
Childhood cancer predisposition
Germline variants
Somatic mutations
Whole-genome sequencing
Journal
The Lancet regional health. Europe
ISSN: 2666-7762
Titre abrégé: Lancet Reg Health Eur
Pays: England
ID NLM: 101777707
Informations de publication
Date de publication:
Apr 2024
Apr 2024
Historique:
received:
20
11
2023
revised:
04
02
2024
accepted:
23
02
2024
medline:
28
5
2024
pubmed:
28
5
2024
entrez:
28
5
2024
Statut:
epublish
Résumé
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. 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. 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 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. The study was supported by the Swedish Childhood Cancer Fund and the Ministry of Health and Social Affairs.
Sections du résumé
Background
UNASSIGNED
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
UNASSIGNED
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
UNASSIGNED
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
Interpretation
UNASSIGNED
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
UNASSIGNED
The study was supported by the Swedish Childhood Cancer Fund and the Ministry of Health and Social Affairs.
Identifiants
pubmed: 38803632
doi: 10.1016/j.lanepe.2024.100881
pii: S2666-7762(24)00047-4
pmc: PMC11129334
doi:
Types de publication
Journal Article
Langues
eng
Pagination
100881Informations de copyright
© 2024 The Author(s).
Déclaration de conflit d'intérêts
BT, FA, ET, and AN received support from the Swedish Childhood Cancer Fund (BT: TJ2018-0042; FA: KP2021-0010; ET: TJ2021-0125; AN: KP2019-0024, PR2019-0027, TJ2019-0013) and the Swedish Cancer Fund (FA: 21 1540 Fk 01 H; ET: 22 2451Fk; AN: 22 2057Pj). BT, ET and AN received support from Region Stockholm (BT: FoUI-985957; ET: FoUI-973659; AN: 5010124 ALF, 520136 ALF). AN received support from The Swedish Research Council (2021-02860). MB received honoraria for lectures by the Swedish Childhood Cancer Fund. GS served as advisor for trial design for Cyxone AB, Sweden. NH served as Chair of NOPHO Scientific Committee and Young NOPHO without retribution. RR received honoraria from AbbVie, AstraZeneca, Janssen, Illumina, and Roche. DG received grants from Swedish Ministry of Health and Social Affairs for GMS Childhood Cancer and is Vice dean for internationalization and recruitment, Faculty of Medicine, Lund University. AN received also funding from the Cancer Society of Stockholm, Stiftelsen Frimurare Barnhuset i Stockholm, Hållsten research foundation, Berth von Kantzow foundation and is board member of Sävstaholm foundation, Ågrenska foundation, Sällsyntafonden. All other authors have no conflict of interest to declare.