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European Journal of Medical Genetics Nov 2020WT1 mutations cause a wide spectrum of renal and extrarenal manifestations concerning urogenital development and the development of tumors.
BACKGROUND
WT1 mutations cause a wide spectrum of renal and extrarenal manifestations concerning urogenital development and the development of tumors.
METHODS
We retrospectively collected the information on the genotype and phenotype of WT1 nephropathy from the multicenter registry since 2014 to 2019. All patients were stratified by renal function decline status or by sequence timing. Rapid progressive group was defined as rapidly developing into ERSD within 12 months since disease onset. Early sequencing group was defined as gene mutation identified before ERSD.
RESULTS
Thirty-three (3.5%) cases were identified with a WT1 mutation in patients with steroid resistant nephrotic syndrome (SRNS), proteinuria and chronic kidney disease (CKD) 3-5 stage of unknown origin. ESRD developed in twenty patients at a median age of 4.3 years old. Comparing study between the rapid progressive group (n = 8) and non-rapid progressive group (n = 25) showed no significant difference in age of onset, gender, syndrome phenotype, genotype and proteinuria except for initial estimated glomerular filtration rate (eGFR) (p = 0.021) or sequencing timing (p = 0.003). In multivariable logistic regression analysis, the delayed sequencing was associated with rapid renal function decline, even after adjusting for established clinical factors including syndromic phenotype, genotype, age onset and eGFR at initial stage (p = 0.019). The renal survival analysis did not show a significantly better outcome in early sequencing group than in delayed sequencing group (p > 0.05).
CONCLUSION
Screening for WT1 mutations should be performed in children with Wilms' tumor, proteinuria/SRNS or CKD. Early diagnosis of WT1 nephropathy through clinical and genetic findings is warranted.
Topics: Child, Preschool; Cohort Studies; Early Diagnosis; Female; Genetic Testing; Humans; Infant; Male; Multicenter Studies as Topic; Nephrotic Syndrome; Proteinuria; Renal Insufficiency, Chronic; WT1 Proteins; Wilms Tumor
PubMed: 32891756
DOI: 10.1016/j.ejmg.2020.104047 -
CEN Case Reports May 2023Wilms tumor 1 (WT1) is the causative gene of Denys-Drash syndrome and Frasier syndrome, and in most cases, kidney failure develops after birth. We report an unusual case...
Wilms tumor 1 (WT1) is the causative gene of Denys-Drash syndrome and Frasier syndrome, and in most cases, kidney failure develops after birth. We report an unusual case of Potter sequence due to fetal nephropathy and kidney failure with a WT1 mutation. The neonate was born at 37 weeks of gestation, and had no distinctive facial appearance or anomalies of the extremities. The external genitalia were ambiguous. Presence of a penile-like structure or hypertrophic clitoris was noted, and the urethra opened at the base of the penis or clitoris. On ultrasonographic examination, the kidney sizes were small. No kidney cysts were noted, but the kidney parenchymal luminosity was increased. Although the neonate received mechanical ventilation because of severe retractive breathing after birth, he died of poor oxygenation due to air leak syndrome at 60 h after birth. The congenital anomalies of the kidney and urinary tract (CAKUT) gene panel revealed a heterozygous missense mutation in WT1 [NM_024426.6:exon9:c.1400G > A, p.(Arg467Gln)]. In WT1, missense mutations are associated with earlier onset of nephropathy than nonsense or splicing mutations. However, severe cases of fetal onset and early neonatal death with WT1 mutations are rare, and only one severe case with the same missense mutation in WT1 has been reported. Therefore, WT1 mutation may be suspected in Potter sequence patients with external genital abnormalities, and the WT1 missense mutation in our case [NM_024426.6:exon9:c.1400G > A, p.(Arg467Gln)] may indicate a severe case with fetal onset of nephropathy and kidney failure.
Topics: Male; Infant, Newborn; Humans; WT1 Proteins; Wilms Tumor; Mutation; Kidney Neoplasms; Renal Insufficiency
PubMed: 36227513
DOI: 10.1007/s13730-022-00742-x -
Cancer Aug 2020A primary objective of Children's Oncology Group study AREN0534 (Treatment for Patients With Multicentric or Bilaterally Predisposed, Unilateral Wilms Tumor) was to... (Clinical Trial)
Clinical Trial
BACKGROUND
A primary objective of Children's Oncology Group study AREN0534 (Treatment for Patients With Multicentric or Bilaterally Predisposed, Unilateral Wilms Tumor) was to facilitate partial nephrectomy in 25% of children with bilaterally predisposed unilateral tumors (Wilms tumor/aniridia/genitourinary anomalies/range of developmental delays [WAGR] syndrome; and multifocal and overgrowth syndromes). The purpose of this prospective study was to achieve excellent event-free survival (EFS) and overall survival (OS) while preserving renal tissue through preoperative chemotherapy, completing definitive surgery by 12 weeks from diagnosis, and modifying postoperative chemotherapy based on histologic response.
METHODS
The treating institution identified whether a predisposition syndrome existed. Patients underwent a central review of imaging studies through the biology and classification study AREN03B2 and then were eligible to enroll on AREN0534. Patients were treated with induction chemotherapy determined by localized or metastatic disease on imaging (and histology if a biopsy had been undertaken). Surgery was based on radiographic response at 6 or 12 weeks. Further chemotherapy was determined by histology. Patients who had stage III or IV disease with favorable histology received radiotherapy as well as those who had stage I through IV anaplasia.
RESULTS
In total, 34 patients were evaluable, including 13 males and 21 females with a mean age at diagnosis of 2.79 years (range, 0.49-8.78 years). The median follow-up was 4.49 years (range, 1.67-8.01 years). The underlying diagnosis included Beckwith-Wiedemann syndrome in 9 patients, hemihypertrophy in 9 patients, multicentric tumors in 10 patients, WAGR syndrome in 2 patients, a solitary kidney in 2 patients, Denys-Drash syndrome in 1 patient, and Simpson-Golabi-Behmel syndrome in 1 patient. The 4-year EFS and OS rates were 94% (95% CI, 85.2%-100%) and 100%, respectively. Two patients relapsed (1 tumor bed, 1 abdomen), and none had disease progression during induction. According to Response Evaluation Criteria in Solid Tumor 1.1 criteria, radiographic responses included a complete response in 2 patients, a partial response in 21 patients, stable disease in 11 patients, and progressive disease in 0 patients. Posttherapy histologic classification was low-risk in 13 patients (including the 2 complete responders), intermediate-risk in 15 patients, and high-risk in 6 patients (1 focal anaplasia and 5 blastemal subtype). Prenephrectomy chemotherapy facilitated renal preservation in 22 of 34 patients (65%).
CONCLUSIONS
A standardized approach of preoperative chemotherapy, surgical resection within 12 weeks, and histology-based postoperative chemotherapy results in excellent EFS, OS, and preservation of renal parenchyma.
Topics: Child; Child, Preschool; Combined Modality Therapy; Drug Therapy; Female; Humans; Infant; Kidney; Male; Neoplasm Metastasis; Nephrectomy; Progression-Free Survival; Treatment Outcome; WAGR Syndrome; Wilms Tumor
PubMed: 32459384
DOI: 10.1002/cncr.32958 -
Journal of Pediatric Urology Oct 2019Given improvements in multimodality therapy, survival among children with Wilms tumor (WT) exceeds 90%. However, 15% of children with favorable histology and 50% of...
BACKGROUND
Given improvements in multimodality therapy, survival among children with Wilms tumor (WT) exceeds 90%. However, 15% of children with favorable histology and 50% of children with anaplastic WT experience recurrence or progression. Of patients with advanced disease, only 50% survive to adulthood. In adult malignancies (including renal tumors), patient survival has improved with the advent of immunotherapy. However, little is known about the immune microenvironment of WT, making the potential role of immunotherapy unclear.
OBJECTIVE
The objective of the study is to perform an exploratory, descriptive analysis of the immune milieu in WT.
STUDY DESIGN
Between 2016 and 2017, all pediatric patients with WT, some of whom received neoadjuvant chemotherapy, underwent ex vivo wedge biopsy at the time of nephrectomy. The fresh tumor tissue and peripheral blood samples were analyzed for infiltrating immune infiltrate and effector cells using flow cytometry. Immunohistochemistry was performed for CD4, CD8, and PD-L1 expression. Matched blood samples were obtained for each patient, and circulating immune cells were analyzed by flow cytometry.
RESULTS
A total of six patients were enrolled. One patient with neuroblastoma was excluded. The remaining five patients included the following: two with unilateral WT (resected before chemotherapy), two with bilateral WT (resected after neoadjuvant chemotherapy), and one with Denys-Drash syndrome, end-stage renal disease, and history of WT in the contralateral kidney. Immune analysis showed that WT were infiltrated by immune cells regardless of chemotherapy status. CD8 and CD4 T cells were present in the tumor tissue and exhibited an activated phenotype. Elevated levels of natural killer (NK) cells were observed in the tumors (Figure). Immune checkpoint PD-L1 was also found expressed in one of the tumors stained.
DISCUSSION
In this pilot study, it was found that WTs were infiltrated by immune cells (CD45+) both before and after chemotherapy. Elevated levels of NK cells infiltrating the tumor specimens, which were quantitatively increased compared with levels of NK cells circulating in the blood, were noted. T cells, particularly CD4+ and CD8+ T cells, were present in tumor specimens. Tumor-infiltrating CD4 and CD8 T cells displayed an activated phenotype as defined by increased expression of human leukocyte antigen-DR isotype (HLA-DR), programmed cell death protein 1 (PD1), and CD57. Together, these findings suggest that WT microenvironment is immune engaged and may be susceptible to immunotherapy similar to other malignancies.
CONCLUSIONS
These pilot data suggest an immune-engaged tumor microenvironment is present within WT. This implies that WT may be susceptible to immunotherapy similar to adult renal tumors and other adult malignancies. Follow-up studies are currently underway.
Topics: Antigens, CD; Biomarkers, Tumor; CD4-CD8 Ratio; Child, Preschool; Female; Follow-Up Studies; Humans; Immunity, Cellular; Immunotherapy; Kidney Neoplasms; Male; Pilot Projects; Prognosis; Retrospective Studies; T-Lymphocytes; Wilms Tumor
PubMed: 30981637
DOI: 10.1016/j.jpurol.2019.03.011 -
Pediatric Nephrology (Berlin, Germany) Apr 2022Wilms tumour (WT) survivors, especially patients with associated syndromes or genitourinary anomalies due to constitutional WT1 pathogenic variant, have increased risk...
BACKGROUND
Wilms tumour (WT) survivors, especially patients with associated syndromes or genitourinary anomalies due to constitutional WT1 pathogenic variant, have increased risk of kidney failure. We describe the long-term kidney function in children with WT and WT1 pathogenic variant to inform the surgical strategy and oncological management of such complex children.
METHODS
Retrospective analysis of patients with WT and constitutional WT1 pathogenic variant treated at a single centre between 1993 and 2016, reviewing genotype, phenotype, tumour histology, laterality, treatment, patient survival, and kidney outcome.
RESULTS
We identified 25 patients (60% male, median age at diagnosis 14 months, range 4-74 months) with WT1 deletion (4), missense (2), nonsense (8), frameshift (7), or splice site (4) pathogenic variant. Thirteen (52%) had bilateral disease, 3 (12%) had WT-aniridia, 1 had incomplete Denys-Drash syndrome, 11 (44%) had genitourinary malformation, and 10 (40%) had no phenotypic anomalies. Patient survival was 100% and 3 patients were in remission after relapse at median follow-up of 9 years. Seven patients (28%) commenced chronic dialysis of which 3 were after bilateral nephrectomies. The overall kidney survival for this cohort as mean time to start of dialysis was 13.38 years (95% CI: 10.3-16.4), where 7 patients experienced kidney failure at a median of 5.6 years. All of these 7 patients were subsequently transplanted. In addition, 2 patients have stage III and stage IV chronic kidney disease and 12 patients have albuminuria and/or treatment with ACE inhibitors. Four patients (3 frameshift; 1 WT1 deletion) had normal blood pressure and kidney function without proteinuria at follow-up from 1.5 to 12 years.
CONCLUSIONS
Despite the known high risk of kidney disease in patients with WT and constitutional WT1 pathogenic variant, nearly two-thirds of patients had sustained native kidney function, suggesting that nephron-sparing surgery (NSS) should be attempted when possible without compromising oncological risk. Larger international studies are needed for accurate assessment of WT1genotype-kidney function phenotype correlation.
Topics: Child; Child, Preschool; Female; Genes, Wilms Tumor; Humans; Infant; Kidney; Kidney Neoplasms; Male; Mutation; Neoplasm Recurrence, Local; Renal Dialysis; Renal Insufficiency; Retrospective Studies; WT1 Proteins; Wilms Tumor
PubMed: 34608521
DOI: 10.1007/s00467-021-05125-5 -
Nucleic Acids Research May 2018Wilms tumor protein (WT1) is a Cys2-His2 zinc-finger transcription factor vital for embryonic development of the genitourinary system. The protein contains a C-terminal...
Wilms tumor protein (WT1) is a Cys2-His2 zinc-finger transcription factor vital for embryonic development of the genitourinary system. The protein contains a C-terminal DNA binding domain with four tandem zinc-fingers (ZF1-4). An alternative splicing of Wt1 can add three additional amino acids-lysine (K), threonine (T) and serine (S)-between ZF3 and ZF4. In the -KTS isoform, ZF2-4 determine the sequence-specificity of DNA binding, whereas the function of ZF1 remains elusive. Three X-ray structures are described here for wild-type -KTS isoform ZF1-4 in complex with its cognate DNA sequence. We observed four unique ZF1 conformations. First, like ZF2-4, ZF1 can be positioned continuously in the DNA major groove forming a 'near-cognate' complex. Second, while ZF2-4 make base-specific interactions with one DNA molecule, ZF1 can interact with a second DNA molecule (or, presumably, two regions of the same DNA molecule). Third, ZF1 can intercalate at the joint of two tail-to-head DNA molecules. If such intercalation occurs on a continuous DNA molecule, it would kink the DNA at the ZF1 binding site. Fourth, two ZF1 units can dimerize. Furthermore, we examined a Denys-Drash syndrome-associated ZF1 mutation (methionine at position 342 is replaced by arginine). This mutation enhances WT1 affinity for a guanine base. X-ray crystallography of the mutant in complex with its preferred sequence revealed the interactions responsible for this affinity change. These results provide insight into the mechanisms of action of WT1, and clarify the fact that ZF1 plays a role in determining sequence specificity of this critical transcription factor.
Topics: Alternative Splicing; Amino Acid Sequence; Amino Acid Substitution; Base Sequence; Binding Sites; Crystallography, X-Ray; DNA; Denys-Drash Syndrome; Genes, Wilms Tumor; Humans; Models, Molecular; Mutation; Mutation, Missense; Nucleic Acid Conformation; Protein Conformation; Transcription Factors; WT1 Proteins; Zinc Fingers
PubMed: 29294058
DOI: 10.1093/nar/gkx1274 -
Journal of Indian Association of... Oct 2014To evaluate the outcome of children with bilateral Wilms' tumor (BWT) treated on All India Institute of Medical Sciences-Wilms Tumor-99 (AIIMS-WT-99) protocol.
PURPOSE
To evaluate the outcome of children with bilateral Wilms' tumor (BWT) treated on All India Institute of Medical Sciences-Wilms Tumor-99 (AIIMS-WT-99) protocol.
MATERIALS AND METHODS
All children with BWT, registered in our solid tumor clinic from August 1999 through December 2010 were included.
RESULTS
Of the 178 fresh cases of Wilms Tumor (WT) treated during this period, 11 (6.2%) had bilateral involvement. All patients except one (12 and 3 cm), had massive bilateral tumors of more than 10 cm on each side. There were eight boys and three girls in the age range 6-30 months. One patient had Denys-Drash syndrome. Twenty renal units were operated upon (12 tumorectomy, five partial nephrectomy, and three nephrectomies), while one patient with inferior vena cava (IVC) thrombus died of renal failure. Tumor spill occurred in three units, lymphnode was positive in two patients. Local recurrence occurred in four patients (six of 18 renal units (33%)-two bilateral and two unilateral). There was one recurrence in the liver that was treated with radio-frequency ablation. The 5-year overall survival (OS) was 90% (95% confidence interval (CI) = 50.8-98.6) and the relapse free survival (RFS) was 38% (95% CI = 6.1-71.6).
CONCLUSION
Massive BWT respond poorly to preoperative chemotherapy, are often not amenable to partial nephrectomy/tumorectomy and have a higher local recurrence rate, giving a poor RFS.
PubMed: 25336802
DOI: 10.4103/0971-9261.142005 -
Journal of Indian Association of... 2019Synchronous Bilateral Wilms tumor (sBWT).
CONTEXT
Synchronous Bilateral Wilms tumor (sBWT).
AIMS
This study aimed to assess the outcome of patients with sBWT treated on SIOP protocol.
SETTINGS AND DESIGN
Retrospective and prospective randomized study.
SUBJECTS AND METHODS
SIOP 93-01 protocol was used to study nine patients of sBWT in a single center and followed up over a period from 2 to 5 years.
STATISTICAL ANALYSIS USED
Unpaired -test and Mann-Whitney U-test were used for analysis.
RESULTS
Of nine patients, six were included in the study as three patients lost to follow-up. Among the six patients, there were four girls and two boys with a median age of 2 years. Mean regression in the size of tumor was 87% in four out of six patients. Tumor with unfavorable histology showed 32% response (ratio of favorable: unfavorable histology 2:1). Event-free survival rate was 81.3% and overall survival was 90% over 2-5 years. Recurrence was seen in two patients of whom one had Denys-Drash syndrome. Mean DTPA glomerular filtration rate was 91.4/ml/min/1.73 m preoperatively and that of 3 months after completion of treatment was 84/ml/min/1.73 m. Health-related quality of life (HRQOL) using Pediatric Quality of Life Inventory and Lansky Play Performance Scale revealed significant improvement results of all functioning domains such as physical, social, emotional, and school subscales with < 0.05 and performance scale ( < 0.04).
CONCLUSIONS
We suggest SIOP protocol for sBWT and bilateral nephron-sparing surgery in two stages. However, long-term follow-up is required to assess the ultimate renal function outcome. HRQOL is an essential guide in improving the conditions of pediatric cancer survivors.
PubMed: 30686888
DOI: 10.4103/jiaps.JIAPS_42_18 -
CMAJ : Canadian Medical Association... Aug 2016Rare diseases often present in the first days and weeks of life and may require complex management in the setting of a neonatal intensive care unit (NICU). Exhaustive...
BACKGROUND
Rare diseases often present in the first days and weeks of life and may require complex management in the setting of a neonatal intensive care unit (NICU). Exhaustive consultations and traditional genetic or metabolic investigations are costly and often fail to arrive at a final diagnosis when no recognizable syndrome is suspected. For this pilot project, we assessed the feasibility of next-generation sequencing as a tool to improve the diagnosis of rare diseases in newborns in the NICU.
METHODS
We retrospectively identified and prospectively recruited newborns and infants admitted to the NICU of the Children's Hospital of Eastern Ontario and the Ottawa Hospital, General Campus, who had been referred to the medical genetics or metabolics inpatient consult service and had features suggesting an underlying genetic or metabolic condition. DNA from the newborns and parents was enriched for a panel of clinically relevant genes and sequenced on a MiSeq sequencing platform (Illumina Inc.). The data were interpreted with a standard informatics pipeline and reported to care providers, who assessed the importance of genotype-phenotype correlations.
RESULTS
Of 20 newborns studied, 8 received a diagnosis on the basis of next-generation sequencing (diagnostic rate 40%). The diagnoses were renal tubular dysgenesis, SCN1A-related encephalopathy syndrome, myotubular myopathy, FTO deficiency syndrome, cranioectodermal dysplasia, congenital myasthenic syndrome, autosomal dominant intellectual disability syndrome type 7 and Denys-Drash syndrome.
INTERPRETATION
This pilot study highlighted the potential of next-generation sequencing to deliver molecular diagnoses rapidly with a high success rate. With broader use, this approach has the potential to alter health care delivery in the NICU.
Topics: Female; Genetic Association Studies; Genetic Testing; High-Throughput Nucleotide Sequencing; Humans; Infant, Newborn; Intensive Care Units, Neonatal; Male; Mutation; Ontario; Pilot Projects; Prospective Studies; Rare Diseases; Retrospective Studies
PubMed: 27241786
DOI: 10.1503/cmaj.150823 -
Cancers Oct 2021(1) Background: about 10% of Wilms Tumor (WT) patients have a malformation or cancer predisposition syndrome (CPS) with causative germline genetic or epigenetic...
(1) Background: about 10% of Wilms Tumor (WT) patients have a malformation or cancer predisposition syndrome (CPS) with causative germline genetic or epigenetic variants. Knowledge on CPS is essential for genetic counselling. (2) Methods: this retrospective analysis focused on 2927 consecutive patients with WTs registered between 1989 and 2017 in the SIOP/GPOH studies. (3) Results: Genitourinary malformations (GU, = 66, 2.3%), Beckwith-Wiedemann spectrum (BWS, = 32, 1.1%), isolated hemihypertrophy (IHH, = 29, 1.0%), Denys-Drash syndrome (DDS, = 24, 0.8%) and WAGR syndrome ( = 20, 0.7%) were reported most frequently. Compared to others, these patients were younger at WT diagnosis (median age 24.5 months vs. 39.0 months), had smaller tumors (349.4 mL vs. 487.5 mL), less often metastasis (8.2% vs. 18%), but more often nephroblastomatosis (12.9% vs. 1.9%). WT with IHH was associated with blastemal WT and DDS with stromal subtype. Bilateral WTs were common in WAGR (30%), DDS (29%) and BWS (31%). Chemotherapy induced reduction in tumor volume was poor in DDS (0.4% increase) and favorable in BWS (86.9% reduction). The event-free survival (EFS) of patients with BWS was significantly ( = 0.002) worse than in others. (4) Conclusions: CPS should be considered in WTs with specific clinical features resulting in referral to a geneticist. Their outcome was not always favorable.
PubMed: 34638500
DOI: 10.3390/cancers13195016