Wilms tumor characteristics in children with heterozygous germline DIS3L2 variants

S E van Peer; T D Treger; J Wegert; J A Hol; J Le Gall; E E Jakkula; J Kamihara; E A Mullen; N Graf; S Behjati; R Al-Saadi; C Duncan; J Schienda; R de Putter; J Brzezinski; A Verschuur; O Michaeli; M V Ortiz; J C Herkert; R Armstrong; E Waanders; R P Kuiper; M M van den Heuvel-Eibrink; M Gessler; M C J Jongmans

doi:10.1016/j.gim.2025.101478

Wilms tumor characteristics in children with heterozygous germline DIS3L2 variants

Genet Med. 2025 Jun 3:101478. doi: 10.1016/j.gim.2025.101478. Online ahead of print.

Authors

S E van Peer¹, T D Treger², J Wegert³, J A Hol⁴, J Le Gall⁵, E E Jakkula⁶, J Kamihara⁷, E A Mullen⁷, N Graf⁸, S Behjati², R Al-Saadi⁹, C Duncan¹⁰, J Schienda¹¹, R de Putter¹², J Brzezinski¹³, A Verschuur¹⁴, O Michaeli¹⁵, M V Ortiz¹⁶, J C Herkert¹⁷, R Armstrong¹⁸, E Waanders¹⁹, R P Kuiper²⁰, M M van den Heuvel-Eibrink²¹, M Gessler²², M C J Jongmans²⁰

Affiliations

¹ Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, the Netherlands. Electronic address: s.e.vanpeer-3@prinsesmaximacentrum.nl.
² Wellcome Sanger Institute, Hinxton, CB10 1SA, UK; Department of Paediatrics, University of Cambridge, Cambridge, CB2 0QQ, UK; Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK.
³ Theodor-Boveri-Institute/Biocenter, Developmental Biochemistry, Wuerzburg University, Wuerzburg, Germany.
⁴ Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, the Netherlands; Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands.
⁵ Department of Genetics, Institut Curie, Paris, France.
⁶ Department of Clinical Genetics, HUSLAB, HUS Diagnostic Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
⁷ Department of Pediatric Oncology, Dana-Farber Cancer Institute/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, Massachusetts, USA.
⁸ Department of Paediatric Oncology and Hematology, Saarland University Hospital, Homburg, Germany.
⁹ Developmental Biology and Cancer Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, University College London, London, UK; Department of Histopathology, Great Ormond Street Hospital for Children, London, UK.
¹⁰ Great Ormond Street Hospital for Children (GOSH), NHS Foundation Trust, London, UK.
¹¹ Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA.
¹² Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
¹³ Division of Haematology/Oncology, Hospital for Sick Children, Toronto, Ontario, Canada.
¹⁴ Pediatric Oncology and Hematology Department, La Timone, Hospital, AP-HM, Marseille, France.
¹⁵ Department of Pediatric Hematology and Oncology, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
¹⁶ Department of Paediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁷ Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
¹⁸ Departments of Medical Genetics, Cambridge University Hospital NHS Foundation Trust, Cambridge, CB2, 0QQ, UK.
¹⁹ Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
²⁰ Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, the Netherlands; Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
²¹ Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, the Netherlands; Division of Child Health, Wilhelmina Children's Hospital/University Medical Center Utrecht, Utrecht, the Netherlands.
²² Theodor-Boveri-Institute/Biocenter, Developmental Biochemistry, Wuerzburg University, Wuerzburg, Germany; Comprehensive Cancer Center Mainfranken, Wuerzburg, Germany.

PMID: 40481679
DOI: 10.1016/j.gim.2025.101478

Abstract

Purpose: Heterozygous germline DIS3L2 pathogenic variants were recently linked to Wilms tumor (WT) predisposition. Limited data on cancer penetrance and characteristics complicate surveillance/management recommendations. This study aims to describe an extended cohort of children with WTs and heterozygous germline (likely) pathogenic DIS3L2 variants ((L)PVs).

Methods: Clinical and tumor data of children with WT and heterozygous germline DIS3L2 (L)PVs were retrospectively collected.

Results: Thirty-four children were identified, including 4 familial cases. Germline (L)PVs included exon 9 deletions (n=28) and other (n=6) (L)PVs. Seventeen parents were confirmed to have the DIS3L2 (L)PV, of whom one had a past WT. Median age at WT diagnosis was 41 months (range: 8-101). A somatic second hit in DIS3L2 was found in 19/20 children with genetic tumor data. Five children had bilateral WTs and 11 had metastases (32%). Eight children had high-risk tumor histology (24%, of which 7 post-chemotherapy blastemal). Three children relapsed or developed a second primary tumor, four children were deceased. Recurring clinical features were lacking.

Conclusions: Children with WTs and heterozygous germline DIS3L2 (L)PVs lack a recognizable phenotype. DIS3L2 (L)PVs are a cause for familial WT, but WT penetrance is likely low. This cohort exhibits a high percentage of metastases and high-risk blastemal tumors, which need further study.

Keywords: DIS3L2, pediatric; Wilms tumor; cancer predisposition; nephroblastoma.