Genet Med. 2025 Jun 3:101478. doi: 10.1016/j.gim.2025.101478. Online ahead of print.
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.
PMID:40481679 | DOI:10.1016/j.gim.2025.101478
