Twenty‐four new cases of WT1 germline mutations and review of the literature: Genotype/phenotype correlations for Wilms tumor development

Abstract

We report here 24 new Wilms tumor (WT) patients with germline WT1 alterations and a synopsis of our own previously described and literature cases in whom age of tumor-onset, gender, and laterality were known. This combined database contains 282 patients, 117 patients with and 165 without WT1 germline alterations. Using this information we have determined the median age of tumor-onset for patients with (12.5 months) and without WT1 gene alterations (36 months). The earliest onset was in patients with truncation (12 mo, 66 patients), followed by missense mutations (18 mo, 30 patients) and deletions (22 mo, 21 patients). Patients with the two most frequent nonsense mutations R362X and R390X and the Denys-Drash syndrome (DDS) hot spot mutation R394W/Q/L had a very early onset (9, 12, and 18 mo, respectively). The highest number of bilateral tumors was observed in the group of truncation mutations, with a higher percentage of bilateral tumors when truncations occurred in the 5' half of the WT1 gene. In addition to genital tract anomalies (GU), early onset nephrotic syndrome with diffuse mesangial sclerosis and stromal-predominant histology, tumor bilaterality, and early age of onset can now be added to the list of risk factors for carrying a germline WT1 mutation.

Clinical and Molecular Characterization of Patients with Heterozygous Mutations in Wilms Tumor Suppressor Gene 1

“…Because of the different approach, our cohort also includes a small subset of patients without proteinuria. Some of our findings are in line with the previously published literature, such as the association of age at proteinuria onset and the initiation of RRT, as well as frequency and bilateralism of WT with type and location of the causative mutation (20,21).…”

Topotecan distribution in an anephric infant with therapy resistant bilateral Wilms tumor with a novel germline WT1 gene mutation

“…Therefore, it could be questioned whether all bilateral Wilms tumors in nonsyndromic patients should be screened on germline mutations of WT1, as we did in our patient. Our patient revealed a germline splice site mutation in [2,7,24,26]. However, Schumacher et al [26] found that an extensive rhabdomyomatous diVerentiation and the presence of WT1 mutations correlate with a tumor subtype that responds poorly to chemotherapy.…”

“…It is estimated that in at least 10% of all Wilms tumor cases, the disease arises in children with clinically well-deWned genetic conditions, including WAGR, Denys-Drash, and Beckwith-Wiedemann syndrome [1,3,15,18,23,27]. It has been suggested that nonsyndromic Wilms tumor patients carry a higher risk of germline WT1 mutations in case of bilateral disease and an early age of onset [24]. In contrast, Perotti et al [23] concluded that early age of diagnosis and bilaterality in Wilms tumor patients without associated abnormalities are no eYcient predictors of germline WT1 aberrations, based on a small group of 20 tumors with only 9 bilateral tumors [23].…”

“…It is conceivable that bilateral Wilms tumor patients, especially if it occurs at an early age of onset, may carry germline WT1 gene mutations more frequently as compared to patients with unilateral Wilms tumor, although previous studies report conXicting observations [19,23,24]. Constitutional defects of the WT1 gene are involved in several overlapping clinical phenotypes, including the WAGR syndrome (Wilms tumor, Aniridia, Genito-urinary malformations and mental Retardation), Denys-Drash and Beckwith Widemann syndrome.…”

Clinical Pictures and Novel Mutations ofWT1-Associated Denys–Drash Syndrome in Two Chinese Children

“…Renal histology revealed that most glomeruli (77.9%) were in an early stage of DMS. The mutation she carried is also a novel mutation for a DDS patient, although it had been reported in some Wilms' tumor patients 14 and in a 46 XY male Frasier syndrome patient. 15 Therefore, it seems that the mutation at this site can cause a broad range of clinical phenotypes.…”