Convergent evolution of 11p allelic loss in multifocal Wilms tumors arising in WT1 mutation carriers

Wilms tumors in patients with constitutional WT1 mutations are examples of Knudson's tumor suppressor paradigm, with somatic inactivation of the second allele occurring through 11p loss of heterozygosity. The time point of this second hit has remained unknown. We analyzed seven Wilms tumors from two patients with constitutional WT1 mutations by whole exome sequencing and genomic array. All tumors exhibited wild type WT1 loss through uniparental isodisomy. Each tumor had a unique genomic breakpoint in 11p, typically accompanied by a private activating mutation of CTNNB1. Hence, convergent evolution rather than field carcinogenesis underlies multifocal tumors in WT1 mutation carriers.     

Pitfalls in the differential diagnosis of renal tumor in an adolescent

The differential diagnosis of renal tumors, particularly in adolescents, may be challenging. We describe an 11‐year‐old female with a primary intra‐renal mass. Initial differential diagnoses included primitive neuroectodermal tumor (PNET), desmoplastic small round cell tumor (DSRCT), and Wilms Tumor (WT). Extensive pathologic and molecular analysis on initial and relapsed tumor samples confirmed WT. The EWS‐WT1 and EWS‐FLI1 rearrangements, distinctive of DSRCT and PNET were negative. The differential diagnosis on monophasic blastemal WT may be complex. Primary renal DSRCT and PNET have been rarely described. Nevertheless, molecular confirmation for these rare conditions may be necessary in selected cases. Pediatr Blood Cancer 2010;54:319–321. © 2009 Wiley‐Liss, Inc.     

Management of Wilms tumors in Drash and Frasier syndromes

Background

Children with WT1 gene‐related disorders such as Denys–Drash syndrome (DDS) and Frasier syndrome (FS) are at increased risk of Wilms tumor and end‐stage renal disease. We investigated whether Wilms tumors in these patients displayed a specific phenotype or behavior and whether nephron‐sparing surgery was beneficial.

Procedure

We retrospectively studied all patients with DDS, FS, or other WT1 mutations treated at our institutions between 1980 and 2007.

Results

We identified 20 patients, of whom 18 had benign or malignant tumors. Wilms tumors occurred in 15 patients, being unilateral in 10 and bilateral in 5 (20 tumors). Median age at Wilms tumor diagnosis was 9 months. No patients had metastases. According to the International Society of Pediatric Oncology Working Classification, there were 19 intermediate‐risk tumors and one high‐risk tumor; no tumor was anaplastic. In patients with nephropathy who underwent unilateral nephrectomy for Wilms tumor or nephron‐sparing surgery for bilateral Wilms tumor, mean time to dialysis was 11 or 9 months, respectively. Other tumors included three gonadoblastomas (in two patients), one retroperitoneal soft‐tissue tumor, and one transitional cell papilloma of the bladder. Two patients, both with stage I Wilms tumor, died from end‐stage renal disease‐related complications. The median follow‐up time for the 18 survivors was 136 months (range, 17–224 months).

Conclusion

Most Wilms tumors in children with WT1‐related disorders were early‐stage and intermediate‐risk tumors, with a young age at diagnosis. In patients without end‐stage renal disease, nephron‐sparing surgery should be considered for delaying the onset of renal failure. Pediatr Blood Cancer 2009;52:55–59. © 2008 Wiley‐Liss, Inc.     

Recent advances in Wilms tumor genetics

The past decade has witnessed substantial growth in our knowledge of the genes and loci that are altered in Wilms tumor. Although Wilms tumor was one of the original paradigms of Knudson's two-hit model of cancer formation, it has become apparent that several genetic events contribute to Wilms tumorigenesis. Recent research has identified targets and regulators of the first Wilms tumor gene, WT1, has uncovered several candidate genes at the second Wilms tumor locus, WT2, and has identified two familial Wilms tumor loci, FWT1 and FWT2. The recent discovery of activating beta-catenin mutations in some Wilms tumors has also implicated the Wnt signaling pathway in this neoplasm. Recurrent abnormalities of other loci, including 16q, 1p, and 7p, have indicated that these sites may harbor Wilms tumor genes. An enhanced understanding of these and other genetic lesions will provide the foundation for novel targeted Wilms tumor therapies.     

儿童肾母细胞瘤基因突变的研究进展

肾母细胞瘤是是小儿泌尿系统最常见的恶性肿瘤.该文综述了肾母细胞瘤发生及预后相关基因方面的研究进展,其中WT1基因、CTNNB1基因及WTX基因与该肿瘤的发生相关,MYCN基因、P53基因与SIX1基因可能与预后相关.     

The prognosis of prechemotherapy blastemal predominant histology subtype in Wilms tumor: A retrospective study in China

Purpose : This study aimed to retrospectively analyze survival outcomes for Chinese patients with prechemotherapy blastemal predominant histology type Wilms tumors (WTs). Methods : We collected and analyzed clinical data concerning patients aged <15 years with favorable histology (FH) WTs treated at the Sun Yat‐Sen University Cancer Center from December 2005 to May 2016, based on the Children's Oncology Group protocol. Pathological specimens were collected through biopsy or surgical resection before initiation of chemotherapy. We analyzed survival outcomes involving different prechemotherapy histology subtypes. Results : We enrolled 97 patients with FH WTs (median follow‐up, 71.5 months; range, 22.2‐170.7). The total recurrence rate was 17.5%, and the subtype recurrence rates were as follows: blastemal predominant (45.5%), mixed (7.5%), epithelial (14.3%), and mesenchymal (9.5%) (P = .010). Five‐year event‐free survival (EFS) and overall survival (OS) rates were 84.9% and 81.4%, respectively. Respective 5‐year EFS and OS rates for subtypes were as follows: blastemal predominant (54.5% and 68.2%), mixed (90.0% and 88.9%), epithelial (85.7% and 85.1%), and mesenchymal (90.5% and 94.7%). Multivariate survival analyses showed that the blastemal predominant subtype was an independent prognostic factor of EFS (P = .001) and OS (P = .017). Conclusions : Our findings showed that prechemotherapy blastemal predominant WTs had higher recurrence and lower EFS and OS rates. Our findings suggested that, albeit with some deficiencies, blastemal predominant histology WT–diagnosed prechemotherapy may have prognostic relevance. Further research into other potential confounding variables are required to determine whether such patients warrant altered risk‐stratified therapy.     

Introduction to the genetics of primary renal tumors in children

Wilms tumor can be explained only partially by the “two hit” model that was originally developed for retinoblastoma. Heterogeneity of two kinds, operates. The first is that four other primary tumors are regularly observed in children, and the second is that Wilms tumor itself appears to represent more than one genetic entity. All five of these primary renal tumors arise from primary or secondary mesenchyme, renal blastema, or renal epithelium. Mesoblastic nephroma, and possibly clear cell sarcoma, may have some genetic affinity with Wilms tumor, but rhabdoid tumor of the kidney and renal carcinoma do not. At least three different genes seem to be important in the origin of Wilms tumor. One, WT1, whose mutations may be associated with aniridia, may follow the “two hit” model in that there are cases in which both copies of the gene are defective or lost, as expected for a tumor suppressor gene. A second gene, which is associated with Beckwith-Wiedemann Syndrome (BWS) and which has not been cloned, appears to be imprinted in females, and may have an oncogene function. It is evidently activated by gain of a paternal allele or by loss of the inactive, but possibly trans-sensing, maternal allele. Activation of the insulin-like growth factor II gene may be a final common pathway for mutation in both WT1 and BWS. A third gene is unlinked to either of the other two, but its location and function are unknown. It shares with WT1 specificity for Wilms tumor, which is not true of the BWS gene. © 1993 Wiley-Liss, Inc.     

Molecular and epidemiologic characterization of Wilms tumor from Baghdad,Iraq

Background

Wilms tumor (WT) is the most common childhood kidney cancer worldwide, yet its incidence and clinical behavior vary according to race and access to adequate healthcare resources. To guide and streamline therapy in the war-torn and resource-constrained city of Baghdad, Iraq, we conducted a first-ever molecular analysis of 20 WT specimens to characterize the biological features of this lethal disease within this challenged population.

Methods

Next-generation sequencing of ten target genes associated with WT development and treatment resistance (WT1, CTNNB1, WTX, IGF2, CITED1, SIX2, p53, N-MYC, CRABP2, and TOP2A) was completed. Immunohistochemistry was performed for 6 marker proteins of WT (WT1, CTNNB1, NCAM, CITED1, SIX2, and p53). Patient outcomes were compiled.

Results

Mutations were detected in previously described WT “hot spots” (e.g., WT1 and CTNNB1) as well as novel loci that may be unique to the Iraqi population. Immunohistochemistry showed expression domains most typical of blastemal-predominant WT. Remarkably, despite the challenges facing families and care providers, only one child, with combined WT1 and CTNNB1 mutations, was confirmed dead from disease. Median clinical follow-up was 40.5 months (range 6–78 months).

Conclusions

These data suggest that WT biology within a population of Iraqi children manifests features both similar to and unique from disease variants in other regions of the world. These observations will help to risk stratify WT patients living in this difficult environment to more or less intensive therapies and to focus treatment on cell-specific targets.

     

The pathophysiology of bilateral and multifocal Wilms tumors: What we can learn from the study of predisposition syndromes

Approximately 5% of patients with Wilms tumor present with synchronous bilateral disease. The development of synchronous bilateral Wilms tumor (BWT) is highly suggestive of a genetic or epigenetic predisposition. Patients with known germline predisposition to Wilms tumor (WT1 variants, Beckwith Wiedemann spectrum, TRIM28 variants) have a higher incidence of BWT. This Children's Oncology Group (COG)-International Society for Pediatric Oncology (SIOP-) HARMONICA initiative review for pediatric renal tumors details germline genetic and epigenetic predisposition to BWT development, with an emphasis on alterations in 11p15.5 (ICR1 gain of methylation, paternal uniparental disomy, and postzygotic somatic mosaicism), WT1, TRIM28, and REST. Molecular mechanisms that result in BWT are often also present in multifocal Wilms tumor (multiple separate tumors in one or both kidneys). We identify priority areas for international collaborative research to better understand how predisposing genetic or epigenetic factors associate with response to neoadjuvant chemotherapy, oncologic outcomes, and long-term renal function outcomes.     

Association between the HER2 expression and histological differentiation in Wilms tumor

Human epidermal growth factor receptors (HER) play a critical role in the branching morphogenesis of renal tubules. In the current study, we analyzed the expression of HER2 in Wilms tumor and assessed the role of this gene in the tumorgenesis of Wilms tumor. During the period from 1960 to 2005, 40 patients with Wilms tumor were treated in our department. Twenty-four of those patients (except those with clear cell sarcoma of the kidney and malignant rhabdoid tumor of the kidney) were collected and assessed. The histological component of each Wilms tumor was divided into three categories (epithelial, blastemal, and mesenchymal) and the extent of HER2 protein expression was analyzed immunohistochemically. The normal kidney tissue accompanied with 12 cases of Wilms tumor was also examined. In the normal kidney, HER2 showed a strong immunoreactivity in the cell membranes of the collecting tubules and in the endothelial cells. Of 24 cases, 15 cases showed an epithelial component, while 24 cases had a blastemal component and 21 cases had a mesenchymal component, respectively. Among the 15 specimens with epithelial cell differentiation, eight (53.3%) showed HER2 immunoreactive epithelial cells. HER2 immunoreactive blastemal cells were present in 11 (45.8%) of 24 specimens with blastemal cells. On the other hand, only 3 (14.3%) of 21 specimens containing mesenchymal cells showed HER2 immunoreactivity. These results suggest that the extent of HER2 expression is associated with epithelial differentiation in Wilms tumor. These histological findings may therefore help to explain the development of Wilms tumor from the standpoint of histological differentiation.     

Irinotecan for relapsed Wilms tumor in pediatric patients: SIOP experience and review of the literature—A report from the SIOP Renal Tumor Study Group

While irinotecan has been studied in various pediatric solid tumors, its potential role in Wilms tumor (WT) is less clear. We evaluated response and outcome of irinotecan‐containing regimens in relapsed WT and compared our results to the available literature. Among 14 evaluable patients, one complete response (CR) and two partial responses (PRs) were observed in patients with initial intermediate‐risk (CR and PR) and blastemal‐type histologies (PR). Two patients were alive at last follow‐up showing no evidence of disease. Our results and the reviewed literature suggest some effectiveness of irinotecan in the setting of relapsed WT.     

A novel tissue‐based ß‐catenin gene and immunohistochemical analysis to exclude familial adenomatous polyposis among children with hepatoblastoma tumors

1 Background

The Wnt/β‐catenin pathway plays a central role in the pathogenesis of most hepatoblastomas (HBs), that is, up to 60–80% carry activating CTNNB1 mutations. HBs can however also be the first manifestation of familial adenomatous polyposis (FAP). As this is a severe disease, it is important for the patient and related family members to firmly exclude FAP at an early stage. Current diagnosis largely depends on APC germline mutation detection on genomic DNA, which is associated with 10–20% false‐negative results. Here, we establish and validate a tissue‐based β‐catenin gene and immunohistochemical analysis, which complements germline mutation screening to exclude the diagnosis of FAP among HB patients.

2 Methods

Tumor tissues of 18 HB patients, including three FAP cases were subjected to CTNNB1 exon 3 mutational analysis and immunohistochemistry comparing staining patterns for total and exon 3 specific β‐catenin antibodies.

3 Results

Our novel tissue‐based method reliably identified all three FAP patients. Their tumors were characterized by a wild‐type exon 3 sequence and a comparable nuclear staining for both antibodies. In contrast, the non‐FAP tumors carried missense CTNNB1 mutations combined with a clearly reduced staining for the exon 3 antibody, or complete loss of staining in case of lesions with exon 3 deletions.

4 Conclusion

We have successfully established and validated a novel ß‐catenin gene and immunohistochemical diagnostic method, which, when combined with routine germline DNA testing, allows the exclusion of the diagnosis of FAP among HB patients.     

Fanconi anemia gene mutations are not involved in sporadic Wilms tumor

Bi‐allelic germline mutations of the Fanconi anemia (FA) genes, PALB2/FANCN and BRCA2/FANCD1, have been reported in a few Wilms tumor (WT) patients with an atypical FA phenotype. Therefore, we screened a random cohort of 47 Dutch WT cases for germline mutations in these two FA‐genes by DNA sequencing and Multiplex Ligation‐dependent Probe Amplification (MLPA). Although several cases appeared to carry missense variants, no bi‐allelic pathogenic mutations were identified, indicating that bi‐allelic mutations in these FA‐genes do not contribute significantly to the occurrence of WT. Pediatr Blood Cancer. 2010;55:742–744. © 2010 Wiley‐Liss, Inc.     

WT1 mutation as a cause of 46 XY DSD and Wilm's tumour: a case report and literature review

Aim: The Wilms’ Tumour gene is thought to have tumour suppressor activity and to play an important role in nephrogenesis, genitourinary development, haematopoiesis and sex determination. WT1 mutations will impair gonadal and urinary tract development and have been demonstrated to cause syndromes of WAGR, Denys–Drash and Fraiser. Methods: To elucidate the role of constitutional mutations of WT1, in the expression of the different clinical feature, we describe a 14‐year‐9‐month nonmosaic XY sex‐reversed woman with pure gonadal dysgenesis (46, XY karyotype, completely female external genitalia, normal Mullerian ducts, absence of Wolffian ducts, streak gonads) who had right kidney removed at 7 months of age because of Wilms’ tumour and was diagnosed as secondary thrombocytopenia (Plt 60–80 × 10⁹/L) since she was 4 years old. We sequenced the genomic DNA of all the 10 exons of the WT1 in which mutations may occur in proposita. Results: A new de novo insertion mutation in the first exon was found. A ‘GCCGCCTCACTCC’ is inserted between codon 138 and 139, resulting in the creation of a stop codon and a truncated protein. Conclusion: The present data provide further evidence to support the role of WT1 in diverse cellular functions.     

Extrarenal testicular Wilms’ tumor in a 3-year-old child

We report an extremely rare case of extrarenal testicular Wilms’ tumor in a 3-year-old boy with intrabdominal undescended left testis. The patient was admitted because of pain and vomiting, with evidence of a huge abdominal mass. At surgery a large tumor arising from the intrabdominal testis was found. Histology showed the classical triphasic Wilms’ tumor elements: epithelial, mesenchymal and blastemal areas. Extrarenal Wilms’ tumors account for only 3 % of all Wilms’ tumors and just ~100 cases have been reported in literature. Testicular origin is anecdotic. We present histomorphological, histogenetic, clinical, diagnostic, prognostic and therapeutic features of this rare tumor.     

Rhabdomyoblastic pulmonary lesions in a patient with Wilms Tumor: choristomas or metastases?

New lesions that occur while patients are receiving treatment for malignant tumors may represent not only difficulties in arriving at the correct diagnosis, but also impact on subsequent therapeutic options. We encountered a patient developing new pulmonary lesions during and after receiving treatment for Stage II Wilms tumor (WT). The presence of mature rhabdomyoblasts in multiple biopsy specimens allowed rational decisions to be made regarding subsequent therapy. This and other published experiences suggest that patients with WT may develop choristomas or have tumors, which undergo cytodifferentiation. Methodologies are now available allowing differentiation of these two processes.     

Bilateral gonadoblastoma with dysgerminoma and pilocytic astrocytoma with WT1 GT‐IVS9 mutation: A 46 XY phenotypic female with Frasier syndrome

Frasier syndrome is characterized by a 46 XY disorder of sex development, nephropathy, and increased risk for gonadoblastoma due to Wilms tumor 1(WT1) mutation in the donor splice site of intron‐9, resulting in the splice form +KTS. Germ cell tumors and gonadoblastomas have been reported previously in Frasier syndrome. We present the clinical, radiological, and genetic (WT1 mutation analysis) of a 46 XY phenotypic female with Frasier syndrome with bilateral gonadoblastoma with dysgerminoma who developed pilocytic astrocytoma. Pediatr Blood Cancer 2009; 53:1349–1351. © 2009 Wiley‐Liss, Inc.     

The podocyte as a target: cyclosporin A in the management of the nephrotic syndrome caused by <Emphasis Type="Italic">WT1</Emphasis> mutations

Children with steroid-resistant nephrotic syndrome secondary to WT1-associated glomerulopathies (WT1-GP) were considered unresponsive to cyclosporin A (CsA). This assumption is challenged by the findings of recent studies. The patients of these studies had different types of WT1 mutations and varying clinical presentations. However, all of them were of young age and the favourable response to CsA might be the result of treatment at an early stage of the disease. The additional administration of angiotensin-converting enzyme inhibitors may have contributed to the positive outcome. We review recent data on the role of WT1 in the development of WT1-GP and discuss putative therapeutic targets explaining the therapeutic effect of CsA.