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

Abstract

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.

LncRNAs and CircRNAs in cancer

“… 195 , 196 However, the causes of external are still obscured, except for genetic predisposition. 197 About 5% of people with Wilms tumor have bilateral disease. 198 Based on the fact that the incidence rate of black Africans is the highest, whereas the Asian's is lowest, it can be deduced that genetic factors are crucial for the etiology of Wilms tumor.…”

Revisiting the Threshold for Cancer Genetics Referral in Patients With Wilms Tumor

“…10,11 Although not heritable, we would consider such individuals to have cancer predisposition because they may be at risk for bilateral or multifocal WT and other tumors such as hepatoblastoma, neuroblastoma, rhabdomyosarcoma, and adrenal cortical carcinoma depending on which tissues harbor the 11p15 epigenetic mutation. It is also possible that the methylation-sensitive multiplex ligation probe amplification (MS-MLPA) assay used by Hol et al 6 was below the level of sensitivity to detect low levels of methylation alterations. A report from the Memorial Sloan Kettering Cancer Center demonstrated 11p15 gain of methylation at IC1 in six of 21 (28%) patients with WT assessed by a quantitative real-time PCR technique that is more sensitive than MS-MLPA.…”

“…Patients with WT1 -related WT present at a younger age than patients with 11p15-related WT. 6,14,15 NRs—These are regions of persistent embryonal tissue that represent precursors of WT, although most NRs regress spontaneously. 16 The presence of multiple or diffusely distributed NRs is termed nephroblastomatosis.…”

“…A report from the Memorial Sloan Kettering Cancer Center demonstrated 11p15 gain of methylation at IC1 in six of 21 (28%) patients with WT assessed by a quantitative real-time PCR technique that is more sensitive than MS-MLPA. 12 Hol et al 6 suggested that universal referral for genetic counseling and testing is warranted for patients with WT, a view shared by other experts. 5,13 However, nearly two thirds of patients did not have an identified genetic predisposition, and many centers do not have the resources of genetic counselors, geneticists, and administrative staff to obtain insurance authorization to conduct the requisite testing.…”

“…The findings of Hol et al 6 provoke us to consider how we approach referrals for genetic testing among patients with WT. A case can be made to refer all patients, although this is not feasible in many settings.…”