Clinical relevance of mutations in the Wilms tumor suppressor 1 gene WT1 and the cadherin-associated protein beta1 gene CTNNB1 for patients with Wilms tumors: results of long-term surveillance of 71 patients from International Society of Pediatric Oncology Study 9/Society for Pediatric Oncology.

BACKGROUND: Mutations in the Wilms tumor (WT) suppressor 1 gene (WT1) and the cadherin-associated protein beta1 gene (CTNNB1) are found predominantly in stromal type WT, defining a genetic subgroup. The clinical relevance of these mutations remains to be determined. METHODS: A long-term follow-up study was performed for 71 patients (International Society of Pediatric Oncology Study 9/Society for Pediatric Oncology; n = 77 tumors) with known molecular genetic status. Eight patients had bilateral disease, including 2 patients with a WT in both kidneys and 5 patients with a WT in 1 kidney and nephrogenic rests (NRs) in the other kidney. The response to preoperative chemotherapy, relapses, metastases, metachronous tumor development, and deaths were evaluated with a median follow-up of 12 years and 4 months. RESULTS: Nineteen patients (n = 24 tumors) had WT1 mutations, and 16 were constitutional mutations. Three patients with germline mutations had second tumor events: Two patients developed a WT in the kidney with NRs 3 years and 11 years after the first tumor; and 1 patient developed second tumors after 2 years, 1 in the kidney with a previous WT and 1 in the kidney with a previous NR. Eighteen of the WT1 mutant tumors were analyzed for CTNNB1 mutations, and all had mutations. A poor volumetric response (progression and <50% reduction) was observed in all patients who had tumors with a WT1 mutation and in 23 of 52 nonmutant tumors. CONCLUSIONS: Patients with WT1 germline mutations had an increased risk for bilateral disease and second tumor events. Therefore, the authors concluded that tumor surveillance until adulthood should be considered. Although tumors with both WT1 and CTNNB1 mutations had a poor volumetric response, there was no significant difference in overall survival in this cohort of patients with and without WT1 mutations.

Ernst Moro (1874-1951)--a great pediatric career started at the rise of university-based pediatric research but was curtailed in the shadows of Nazi laws.

Ernst Moro was born on December 8, 1874, in Ljubljana, the capital of Slovenia, then part of the Austro-Hungarian empire and attended university in Graz, Austria. Pediatrics, initially regarded as a part of internal medicine, was in its early days as an independent field at universities in German-speaking Europe. The first Chair of Pediatrics had been established in Vienna, Austria in 1884. Ten years later Germany was granted its first Chair in Berlin. Escherich, who held the first Chair of Pediatrics at Graz, was seen as one of the most respected pediatricians in Europe. Therefore, he was invited in 1904 to represent pediatrics together with the American Abraham Jacobi at the International World Congress on Science at the Saint Louis World Exposition in the United States. The high mortality of nearly 25% in infancy was seen as one of the main problems. Escherich's scientific work had established him as the leading bacteriologist. Moro's pediatric career started in Escherich's laboratory with experimental research on the physiology of digestion in infants. In 1900 he presented the first bacteriological characterisation of Lactobacillus acidophilus. In 1906 he received his venia legendi for his work on the bacterial flora in physiological and pathological conditions of the infantile intestine. In 1908 Moro won international reputation for his simple percutaneous skin test for tuberculosis, which was widely used in many countries as the "Moro test" at least until the 1960s. He described a carrot soup and other dietary prescriptions as helpful for diarrhoeal disease. In 1911 he became Head of the Children's Hospital at Heidelberg. In 1918 he described some features peculiar to the first 3 months; according to him this trimenon should be regarded as an own entity like the newborn period. The most famous part of the paper was the description of a milestone in the infant's neurological development, the Umklammerungsreflex (embracing reflex). In 1919 Moro was promoted from associate professor to the first 'Ordinarius', thus founding the first Chair of Pediatrics at Heidelberg and marking the beginning of a scientifically most fruitful period of international collaboration. However, as his wife was of Jewish origin, Moro slowly withdrew from hospital service starting in 1933. After early retirement in 1936, he worked as a pediatrician at home until 1948.

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

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.

Two molecular subgroups of Wilms' tumors with or without WT1 mutations.

PURPOSE: Wilms' tumors (WTs) exhibit more than one pattern of differentiation, each of which is associated with distinctive clinical features and treatment responses. Mutations in the WT1 gene are found predominantly in WTs with stromal histology. To better understand the biological and clinical features in different WTs, we have analyzed WTs with and without WT1 mutations for a set of parameters. EXPERIMENTAL DESIGN: Twenty-two new WTs were analyzed for WT1 mutations by PCR single-strand conformational polymorphism. Five tumors with WT1 mutations and six tumors without WT1 mutations were studied for the presence of WT1 transcripts and protein as well as for the expression of differentiation markers. RESULTS: Two new WT1 mutations were identified in stromal-predominant tumors, and none were identified in the other histological subtypes. Tumors with WT1 mutations expressed mutant messages, cytoplasmic truncated WT1 proteins, and muscle markers. In contrast, blastemal-predominant tumors without mutations showed nuclear WT1 protein staining. Both tumor types were positive for markers of early-induced mesenchyme and one marker of uninduced mesenchyme, but blastemal-predominant tumors also expressed cytokeratin, suggesting that these are further along the epithelial differentiation pathway. CONCLUSIONS: Our data show that the two-hit inactivation of WT1 is operative in stromal-predominant WTs. Cells without functional nuclear WT1 protein start a faulty differentiation program. In contrast, blastemal-predominant tumors express wild-type WT1 and show early signs of epithelialization. The extensive rhabdomyomatous differentiation and the presence of WT1 mutations may be used as a diagnostic tool to identify a tumor subtype that seems to respond poorly to chemotherapy. These studies provide a foundation for improvement in tumor classification and ultimately for the development of more individualized tumor treatments.