Wilms tumor characteristics in children with heterozygous germline DIS3L2 variants

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 DIS3L2 (likely) pathogenic 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 1 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 of 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; 4 children were deceased. Recurring clinical features were lacking. Conclusion: 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.