Germline (epi)genetics reveals high predisposition in females: a 5-year, nationwide, prospective Wilms tumour cohort

• Published in: Journal of medical genetics Vol. 60; no. 9; pp. 842 - 849
• Main Authors: Stoltze, Ulrik Kristoffer, Hildonen, Mathis, Hansen, Thomas Van Overeem, Foss-Skiftesvik, Jon, Byrjalsen, Anna, Lundsgaard, Malene, Pignata, Laura, Grønskov, Karen, Tumer, Zeynep, Schmiegelow, Kjeld, Brok, Jesper Sune, Wadt, Karin A W
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd 01.09.2023; BMJ Publishing Group LTD; BMJ Publishing Group
• Series: Original research
• Subjects: Beckwith-Wiedemann syndrome; biological evolution; Birth weight; Cancer; Cancer Genetics; Cdc4 protein; Chromosome 11; Chromosomes; Disease; DNA methylation; DNA sequencing; Epigenetics; Families & family life; Family medical history; Females; Genes; Genetic counseling; Genetics; Genomes; Genomics; Genotypes; Imprinting; medical oncology; Patients; Pediatrics; Phenotypes; Tumors; Uniparental disomy; Whole genome sequencing; medical oncology; DNA methylation; biological evolution; genetics; pediatrics
• ISSN: 0022-2593; 1468-6244
• DOI: 10.1136/jmg-2022-108982

BackgroundStudies suggest that Wilms tumours (WT) are caused by underlying genetic (5%–10%) and epigenetic (2%–29%) mechanisms, yet studies covering both aspects are sparse.MethodsWe performed prospective whole-genome sequencing of germline DNA in Danish children diagnosed with WT from 2016 to 2021, and linked genotypes to deep phenotypes.ResultsOf 24 patients (58% female), 3 (13%, all female) harboured pathogenic germline variants in WT risk genes (FBXW7, WT1 and REST). Only one patient had a family history of WT (3 cases), segregating with the REST variant. Epigenetic testing revealed one (4%) additional patient (female) with uniparental disomy of chromosome 11 and Beckwith-Wiedemann syndrome (BWS). We observed a tendency of higher methylation of the BWS-related imprinting centre 1 in patients with WT than in healthy controls. Three patients (13%, all female) with bilateral tumours and/or features of BWS had higher birth weights (4780 g vs 3575 g; p=0.002). We observed more patients with macrosomia (>4250 g, n=5, all female) than expected (OR 9.98 (95% CI 2.56 to 34.66)). Genes involved in early kidney development were enriched in our constrained gene analysis, including both known (WT1, FBXW7) and candidate (CTNND1, FRMD4A) WT predisposition genes. WT predisposing variants, BWS and/or macrosomia (n=8, all female) were more common in female patients than male patients (p=0.01).ConclusionWe find that most females (57%) and 33% of all patients with WT had either a genetic or another indicator of WT predisposition. This emphasises the need for scrutiny when diagnosing patients with WT, as early detection of underlying predisposition may impact treatment, follow-up and genetic counselling.