Prevalence of (Epi)genetic Predisposing Factors in a 5-Year Unselected National Wilms Tumor Cohort: A Comprehensive Clinical and Genomic Characterization
Hol, Janna A.; Kuiper, Roland P.; Van Dijk, Freerk; Waanders, Esmé; Van Peer, Sophie E.; Koudijs, Marco J.; Bladergroen, Reno; Van Reijmersdal, Simon V.; Morgado, Lionel M.; Bliek, Jet; Lombardi, Maria Paola; Hopman, Saskia; Drost, Jarno; De Krijger, Ronald R.; Van Den Heuvel-Eibrink, Marry M.; Jongmans, Marjolijn C.J.
(2022) Journal of Clinical Oncology, volume 40, issue 17, pp. 1892 - 1902
(Article)
Abstract
PURPOSEWilms 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 METHODSAll children diagnosed with
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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.RESULTSA 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.
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Keywords: Adult, Beckwith-Wiedemann Syndrome/diagnosis, Causality, Child, Genetic Predisposition to Disease, Genomics, Germ-Line Mutation, Humans, Kidney Neoplasms/epidemiology, Prevalence, Wilms Tumor/epidemiology, Oncology, Cancer Research, Journal Article
ISSN: 0732-183X
Publisher: American Society of Clinical Oncology
Note: Funding Information: Supported by Stichting Kinderen Kankervij (Foundation KiKa), Grant No. 278 to M.M.v.d.H.E., M.C.J.J., and R.P.K. The support of the renal tumor team members in the Princess Máxima Center for Pediatric Oncology is highly appreciated. Publisher Copyright: © American Society of Clinical Oncology.
(Peer reviewed)