TY - JOUR
T1 - Prevalence of (Epi)genetic Predisposing Factors in a 5-Year Unselected National Wilms Tumor Cohort
T2 - A Comprehensive Clinical and Genomic Characterization
AU - Hol, Janna A.
AU - Kuiper, Roland P.
AU - van Dijk, Freerk
AU - Waanders, Esmé
AU - van Peer, Sophie E.
AU - Koudijs, Marco J.
AU - Bladergroen, Reno
AU - van Reijmersdal, Simon V.
AU - Morgado, Lionel M.
AU - Bliek, Jet
AU - Lombardi, Maria Paola
AU - Hopman, Saskia
AU - Drost, Jarno
AU - de Krijger, Ronald R.
AU - van den Heuvel-Eibrink, Marry M.
AU - Jongmans, Marjolijn C. J.
N1 - 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.
PY - 2022/6/10
Y1 - 2022/6/10
N2 - 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 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.
AB - 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 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.
UR - http://www.scopus.com/inward/record.url?scp=85131136662&partnerID=8YFLogxK
U2 - https://doi.org/10.1200/JCO.21.02510
DO - https://doi.org/10.1200/JCO.21.02510
M3 - Article
C2 - 35230882
SN - 0732-183X
VL - 40
SP - 1892
EP - 1902
JO - Journal of clinical oncology
JF - Journal of clinical oncology
IS - 17
ER -