Pediatric Wilms Tumor Research Articles

Renal Tumors in Children Aged 10–16 Years: A Report from the United Kingdom Children's Cancer and Leukaemia Group

Wilms tumor is the most common renal tumor of childhood. However, other epithelial, mesenchymal, and neuroectodermal neoplasms may also arise in the kidney during childhood, several of which show specific age distributions; in the 1st year of life, mesoblastic nephroma and rhabdoid tumor are more common, whereas renal cell carcinoma, primitive neuroectodermal tumor, and anaplastic Wilms tumors are relatively more frequent in older children and adolescents. The aim of this study is to describe the spectrum of renal tumors in children aged 10-16 years using data from 1492 patients registered in the UK Wilms Tumour 3 Trial (1991-2001) and International Society of Paediatric Oncology Wilms Tumour Trial 2001 (2002-2008) clinical trials of renal tumors in childhood. There were 67 (4.6%) tumors in children aged 10-16 years: 50 Wilms tumors (74.6%), 10 (14.9%) renal cell carcinomas, 3 (4.5%) renal medullary carcinomas, 2 (3%) primitive neuroectodermal tumors, 1 clear cell sarcoma of kidney, and 1 desmoplastic small round cell tumor. Fourteen percent of the Wilms tumors in this age group had diffuse anaplasia. Among the 10 renal cell carcinomas, 4 were associated with t(Xp-11.2), 3 were of papillary type II, 1 was papillary type I, 1 was clear cell type, and 1 was unclassified. Five-year overall survival for Wilms tumor was 63% (43% for anaplastic tumors), significantly lower than reported overall survival for all pediatric Wilms tumors. Only 40% of patients with renal cell carcinoma survived, and all patients with other tumors died.

Immunohistochemical Expression of Neural Cell Adhesion Molecule in Wilms Tumors, Nephrogenic Rests, and Fetal and Postnatal Renal Cortices

Neural cell adhesion molecule (NCAM) has been suggested to be a marker for stem cells and progenitor cells in human fetal kidney and Wilms tumors. In this tissue microarray-based immunohistochemical study, we confirmed the expression of NCAM in Wilms tumors, nephrogenic rests, and metanephric mesenchyme and its early derivatives in fetal renal cortex. Neural cell adhesion molecule expression was noted in both favorable-histology and unfavorable-histology Wilms tumors. This indicates that NCAM may be an attractive therapeutic target in chemoresistant, high-risk Wilms tumors. In addition, we saw rare NCAM-positive interstitial stromal cells in postnatal kidney. It is not known if these persistent NCAM-positive interstitial cells might give rise to adult Wilms tumors and cases of pediatric Wilms tumors not associated with nephrogenic rests.

Loss of heterozygosity and SOSTDC1 in adult and pediatric renal tumors

BackgroundDeletions within the short arm of chromosome 7 are observed in approximately 25% of adult and 10% of Wilms pediatric renal tumors. Within Wilms tumors, the region of interest has been delineated to a 2-Mb minimal region that includes ten known genes. Two of these ten candidate genes, SOSTDC1 and MEOX2, are particularly relevant to tumor development and maintenance. This finding, coupled with evidence that SOSTDC1 is frequently downregulated in adult renal cancer and regulates both Wingless-Int (Wnt)- and bone morphogenetic protein (BMP)-induced signaling, points to a role for SOSTDC1 as a potential tumor suppressor.MethodsTo investigate this hypothesis, we interrogated the Oncomine database to examine the SOSTDC1 levels in adult renal clear cell tumors and pediatric Wilms tumors. We then performed single nucleotide polymorphism (SNP) and sequencing analyses of SOSTDC1 in 25 pediatric and 36 adult renal tumors. Immunohistochemical staining of patient samples was utilized to examine the impact of SOSTDC1 genetic aberrations on SOSTDC1 protein levels and signaling.ResultsWithin the Oncomine database, we found that SOSTDC1 levels were reduced in adult renal clear cell tumors and pediatric Wilms tumors. Through SNP and sequencing analyses of 25 Wilms tumors, we identified four with loss of heterozygosity (LOH) at 7p and three that affected SOSTDC1. Of 36 adult renal cancers, we found five with LOH at 7p, two of which affected SOSTDC1. Immunohistochemical analysis of SOSTDC1 protein levels within these tumors did not reveal a relationship between these instances of SOSTDC1 LOH and SOSTDC1 protein levels. Moreover, we could not discern any impact of these genetic alterations on Wnt signaling as measured by altered beta-catenin levels or localization.ConclusionsThis study shows that genetic aberrations near SOSTDC1 are not uncommon in renal cancer, and occur in adult as well as pediatric renal tumors. These observations of SOSTDC1 LOH, however, did not correspond with changes in SOSTDC1 protein levels or signaling regulation. Although our conclusions are limited by sample size, we suggest that an alternative mechanism such as epigenetic silencing of SOSTDC1 may be a key contributor to the reduced SOSTDC1 mRNA and protein levels observed in renal cancer.

Beta‐catenin expression and mutation in adult and pediatric Wilms' tumors

Wilms' tumor is the most common pediatric renal neoplasm, but its occurrence in adults is very rare. In contrast to pediatric Wilms' tumor (PWT), very little is known about the pathogenesis of adult Wilms' tumor (AWT). Despite there currently being no morphological difference between AWT and PWT, a cytogenetic study has suggested that the pathogenesis of AWT might be different from that of PWT. Although dysregulation of the Wnt pathway has been implicated in PWT, its role in AWT has never been investigated. To investigate the role of dysregulation of the Wnt pathway in AWT, tumor samples from 4 AWTs and 19 PWTs were surveyed for subcellular localization of beta-catenin by immunohistochemistry and potential mutation of the beta-catenin gene by sequencing. Nuclear translocation of beta-catenin was found in one out of four cases of AWT, but none of them carried mutation of the beta-catenin gene. By comparison, nuclear translocation for beta-catenin and mutation of the beta-catenin gene were present in 53% (10/19) and 15.8% (3/19) of PWTs, respectively. Of the three mutations identified, we found a novel mutation combining a silent mutation (TCT to TCC, Ser37Ser) and an in-frame six-base-pair deletion (del GGTGCC, del Gly38Ala39). This report suggests that dysregulation of the Wnt pathway might also play a role in the pathogenesis of AWT.

Target genes of the WNT/β‐catenin pathway in Wilms tumors

The WNT/beta-catenin pathway is involved in numerous human cancers. Mutations of the CTNNB1 (beta-catenin) gene have also been detected in a subset of pediatric Wilms tumors, but the target genes of the deregulated WNT/beta-catenin pathway in these tumors have yet to be identified. To compare gene expression profiles of Wilms tumors with and without mutations of CTNNB1, we used 11.5-k cDNA microarrays. Most of the tumors (86%) had received preoperative chemotherapy as mandated by the European SIOP protocol. The comparison between Wilms tumors with and without CTNNB1 mutations revealed several target genes specifically deregulated in CTNNB1-mutated Wilms tumors. Among these, PITX2, APCDD1, and two members of the endothelin axis (EDN3 and EDNRA) are directly activated downstream targets of the WNT/beta-catenin pathway that may enhance proliferation of these tumor cells. In addition, several upstream inhibitors of WNT/beta-catenin signaling like WIF1 and PRDC were also strongly up-regulated in the CTNNB1-mutated Wilms tumors. This overexpression may be a negative feedback mechanism in tumors with uncontrolled WNT signaling. Moreover, we identified deregulated genes in both the retinoic acid and the RAS pathways, such as ATX/ENPP2 and RIS1, suggesting an association between these two pathways with that of WNT. In addition, the strong representation of muscle-related genes in the expression profile of CTNNB1-mutated Wilms tumors corresponded to histologically detectable areas of myomatous cells in these tumors that displayed intense and preferential nuclear beta-catenin antibody staining. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.

CT-guided radiofrequency ablation of pediatric Wilms tumor in a solitary kidney

Although recent results of percutaneous imaging-guided radiofrequency ablation (RFA) of various tumors in adults are promising, RFA of tumors in children has been performed in only a small number of cases. We describe the treatment of Wilms tumor in a solitary kidney in a 5-year-old girl using percutaneous CT-guided RFA. The procedure provided short-term palliation in this child for whom partial or total nephrectomy carried high risk and low likelihood of success. Although it might only be useful ultimately as a temporizing measure, oncologists and surgeons might wish to consider RFA in children who would otherwise require dialysis and renal transplantation or who are poor surgical candidates. Various specific technical issues differentiate pediatric from adult tumor ablation, including the amount of intra-abdominal fat, need for smaller grounding pads, and potential systemic effects of tissue heating.

Decrease in LDL receptor-related protein expression and function correlates with advanced stages of Wilms tumors

The molecular processes responsible for the invasive phenotype of pediatric Wilms tumors (WT) are poorly understood. A candidate WT suppressor gene (WT1) has been found mutated in a number of these pediatric kidney tumors. However, the disruption of normal WT1 protein function cannot solely explain WT growth. The aim of the present study is to identify new molecular players that regulate the invasive character of WT. Fresh frozen samples from 45 renal tumors of Wilms were obtained from the National Wilms Tumor Study Group's Biological Samples Bank. Gelatin zymography, Western blotting, and immunodetection were used to compare tissue biopsies originating from the infiltrating (stage III), metastatic (stage IV), and anaplastic phenotype of Wilms tumors (WT). The expression of the low-density lipoprotein receptor-related protein (LRP) diminished in stage IV and anaplastic WT. Moreover, the expression of RAP, an LRP intracellular chaperone, was also decreased. The diminished expression of LRP and RAP correlated with increased levels of several known extracellular ligands that LRP usually recycles from the extracellular matrix (ECM) environment, including PAI-1, MMP-9, and TIMP-1. The proteolytic processing of MT1-MMP, a functional regulator of LRP, also correlated with the WT invasive phenotype. The low expression of LRP, whose function is regulated by MT1-MMP and whose activity in recycling ECM-associated proteolytic enzymes becomes drastically diminished in advanced stages of WT, may in part explain the acquired invasive potential of the developing WT pediatric cancer.

Pediatric genitourinary tumors.

Each year advances are made in the clinical evaluation and treatment of genitourinary tumors in children. Understanding of cellular, molecular, and genetic processes in tumorigenesis is evolving rapidly. In addition, information is accumulating about the long-term outcome and complications associated with treatment modalities. This article reviews the 2001 literature on pediatric Wilms tumor, other renal tumors, rhabdomyosarcoma of the pelvis, paratesticular rhabdomyosarcoma, and testicular tumors. The emphasis in molecular biology is to identify molecular or genetic markers that predict outcome. The National Wilms' Tumor Study Group reported on the complications of surgery and the decreased complication rate when these procedures are performed by pediatric surgical specialists. Long-term complications of treatment are also discussed, including short stature and leukemia. The Intergroup Rhabdomyosarcoma Study Group reported on the results of treatment for nonmetastatic disease and the goals of the upcoming Study V, reduction of chemotherapy and radiotherapy. They also presented data from Study IV and discussed the findings on improved prognosis.

Assignment1 of the chicken NOV gene (alias CCN3) to chromosome 2q34→q36: Conserved and compared synteny between avian, mouse and human

The nephroblastomas induced by the integration of MAV1(N) (avian myeloblastosis-associated virus type 1 N) (Perbal et al., 1985; Soret et al., 1989) in the chicken genome was found to be an attractive model for the study of genes responsible for initiation and establishment of the human pediatric Wilms tumor (Perbal, 1995). Screening of lambda libraries of tumor DNAs allowed us to discover the NOV (nephroblastoma overexpressed) gene (Joliot et al., 1992) whose expression was found to be altered both in avian and human nephroblastomas (Chevalier et al., 1998). The NOV protein belongs to the CCN family of multimodular secreted regulators of cell growth (for a recent review see Perbal, 2001). In normal conditions its expression is associated with polarized differentiation of several different tissues. In human tumors, increased expression of NOV is either a marker of heterotypic differentiation (Chevalier et al., 1998) or associated with increased tumorigenic potential (Manara et al., 2002). Recently, NOV was reported to act as a tumor suppressor in glioblastoma cells (Gupta et al., 2001). The human NOV homolog was previously assigned to human chromosome 8q24 (Martinerie et al., 1992). In the framework of our continued study of the MAV1-(N) integration sites, we report here the localization of the chicken NOV gene on chicken chromosome 2q by fluorescent in situ hybridization. Materials and methods

Detection of a novel t(6;15)(q21;q21) in a pediatric Wilms tumor

We report a novel cytogenetic finding in a favorable histology Wilms tumor occurring in a 4-month-old boy. Karyotypic analysis demonstrated a t(6;15)(q21;q21) in all tumor cells examined. This was confirmed using fluorescence in situ hybridization analysis. Molecular analysis of this rearrangement may provide clues to understanding the pathobiology of Wilms tumor.