Prevalence of (Epi)genetic Predisposing Factors in a 5-Year Unselected National Wilms Tumor Cohort: A Comprehensive Clinical and Genomic Characterization.

Autor:	Hol JA; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands., Kuiper RP; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.; Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands., van Dijk F; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands., Waanders E; Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands., van Peer SE; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands., Koudijs MJ; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.; Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands., Bladergroen R; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands., van Reijmersdal SV; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands., Morgado LM; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands., Bliek J; Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands., Lombardi MP; Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands., Hopman S; Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands., Drost J; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.; Oncode Institute, Utrecht, the Netherlands., de Krijger RR; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.; Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands., van den Heuvel-Eibrink MM; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands., Jongmans MCJ; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.; Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
Jazyk:	angličtina
Zdroj:	Journal of clinical oncology : official journal of the American Society of Clinical Oncology [J Clin Oncol] 2022 Jun 10; Vol. 40 (17), pp. 1892-1902. Date of Electronic Publication: 2022 Mar 01.
DOI:	10.1200/JCO.21.02510
Abstrakt:	Purpose: Wilms tumor (WT) is associated with (epi)genetic predisposing factors affecting a growing number of WT predisposing genes and loci, including those causing Beckwith-Wiedemann spectrum (BWSp) or WT1 -related syndromes. To guide genetic counseling and testing, we need insight into the prevalence of WT predisposing (epi)genetic factors. Patients and Methods: All children diagnosed with WT in the Netherlands between 2015 and 2020 were referred to a clinical geneticist. Phenotypic data, disease characteristics, and diagnostic test results were collected. If no genetic predisposition was identified by targeted diagnostic testing, germline (trio-)whole-exome sequencing and BWSp testing on normal kidney-derived DNA were offered. Results: A total of 126 cases were analyzed of 128 identified patients. (Epi)genetic predisposing factors were present in 42 of 126 patients (33.3%) on the basis of a molecular diagnosis in blood-derived DNA (n = 26), normal kidney-derived DNA (n = 12), or solely a clinical diagnosis of BWSp (n = 4). Constitutional, heterozygous DIS3L2 variants were identified as a recurrent predisposing factor in five patients (4%), with a second somatic hit in 4 of 5 tumors. Twenty patients (16%) were diagnosed with BWSp while four additional patients without BWSp features harbored chromosome 11p15 methylation defects in normal kidney tissue. Remaining findings included WT1 -related syndromes (n = 10), Fanconi anemia (n = 1), neurofibromatosis type 1 (n = 1), and a pathogenic REST variant (n = 1). In addition, (likely) pathogenic variants in adult-onset cancer predisposition genes ( BRCA2 , PMS2 , CHEK2 , and MUTYH ) were identified in 5 of 56 (8.9%) patients with available whole-exome sequencing data. Several candidate WT predisposition genes were identified, which require further validation. Conclusion: (Epi)genetic WT predisposing factors, including mosaic aberrations and recurrent heterozygous DIS3L2 variants, were present in at least 33.3% of patients with WT. On the basis of these results, we encourage standard genetic testing after counseling by a clinical geneticist. Competing Interests: Jarno DrostPatents, Royalties, Other Intellectual Property: WO2016/083613; culture medium for epithelial stem cells and Organoids comprising said stem cells. WO2016/083612; culture medium for expanding breast epithelial stem cellsNo other potential conflicts of interest were reported.
Databáze:	MEDLINE
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