Role of Wilms\u27 Tumor 1 in Sex Development

https://openworks.mdanderson.org/sumexp22/1029/thumbnail.jp

Genetic and Epigenetic Features of Bilateral Wilms Tumor Predisposition in Patients From the Children’s Oncology Group AREN18B5-Q

Developing synchronous bilateral Wilms tumor suggests an underlying (epi)genetic predisposition. Here, we evaluate this predisposition in 68 patients using whole exome or genome sequencing (n = 85 tumors from 61 patients with matched germline blood DNA), RNA-seq (n = 99 tumors), and DNA methylation analysis (n = 61 peripheral blood, n = 29 non-diseased kidney, n = 99 tumors). We determine the predominant events for bilateral Wilms tumor predisposition: 1)pre-zygotic germline genetic variants readily detectable in blood DNA [WT1 (14.8%), NYNRIN (6.6%), TRIM28 (5%), and BRCA-related genes (5%)] or 2)post-zygotic epigenetic hypermethylation at 11p15.5 H19/ICR1 that may require analysis of multiple tissue types for diagnosis. Of 99 total tumor specimens, 16 (16.1%) have 11p15.5 normal retention of imprinting, 25 (25.2%) have 11p15.5 copy neutral loss of heterozygosity, and 58 (58.6%) have 11p15.5 H19/ICR1 epigenetic hypermethylation (loss of imprinting). Here, we ascertain the epigenetic and genetic modes of bilateral Wilms tumor predisposition

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo

Oncolog, Volume 34, Number 02, April-June 1989

Bone Marrow Transplantation Supports Patients through High-Dose Chemotherapy Genetic Linkage Analysis of Familial Wilms\u27 Tumor Osteosarcoma: Expandable Prostheses and Allografts Reduce the Need for Amputationhttps://openworks.mdanderson.org/oncolog/1024/thumbnail.jp

Generation And Use Of A Glycoprotein B Amber Mutant Of Herpes Simplex Virus Type 1.

Amber termination mutants contain a mutation in the coding region of a gene which creates a codon specifying the termination of protein synthesis. Translation of the mutant gene is prematurely terminated at the amber termination codon, resulting in a truncated protein. In the presence of an amber codon-suppressing tRNA, an amino acid is inserted at the amber codon and a protein of normal length is produced. The existence of effective suppressor systems in prokaryotes and thus the ability to propagate otherwise lethal mutants, has made termination mutants invaluable tools in prokaryotic genetics. Recent developments in site-directed mutagenesis and mammalian suppressor systems have made it feasible to generate amber mutants of animal viruses. To investigate ways to generate and use amber mutants in viral research, amber mutations were introduced into the herpes simplex virus type 1 (HSV-1) gene encoding the glycoprotein, gB. Located in the viral envelope, gB is involved in the entry of virus into host cells and is essential for the production of infectious virus particles. Amber mutations were introduced into cloned gB gene by oligonucleotide-directed mutagenesis and Xba I linker insertion. A virus, ambB1, was generated which contained an amber mutation in the cytoplasmic domain-encoding portion of the gB gene. Translation of the mutant gene was predicted to produce a gB molecule missing the final 41 amino acids, or 38% of the putative cytoplasmic domain. Surprisingly, AmbB1 was viable under non-suppressing conditions. Additionally, no alterations in viral plaque morphology was observed and the rate at which ambB1 virions entered host cells was normal. Analysis of cyanogen bromide peptides from ambB1 gB indicated that a truncated protein was synthesized. These data suggest that truncation of the final 41 amino acids of gB does not affect its function. This work demonstrates ways in which amber codons can be introduced at specific locations within a gene and the resulting mutants can be used to investigate protein function. This and other work, along with the recent development of effective suppressing host cells, will further the use of termination mutants in viral research.Ph.D.Biological SciencesMolecular biologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/128013/2/8712136.pd

Wilms tumor genetics: Mutations inWT1,WTX, andCTNNB1 account for only about one-third of tumors

Centro cívico deportivo en las Palmas de Gran Canari

Characterization of the Inflammatory Microenvironment and Identification of Potential Therapeutic Targets in Wilms Tumors

The role of inflammation in cancer has been reported in various adult malignant neoplasms. By contrast, its role in pediatric tumors has not been as well studied. In this study, we have identified and characterized the infiltration of various inflammatory immune cells as well as inflammatory markers in Wilms tumor (WT), the most common renal malignancy in children. Formalin-fixed paraffin-embedded blocks from tumors and autologous normal kidneys were immunostained for inflammatory immune cells (T cells, B cells, macrophages, neutrophils, and mast cells) and inflammatory markers such as cyclooxygenase-2 (COX-2), hypoxia-inducible factor 1α, phosphorylated STAT3, phosphorylated extracellular signal–related kinases 1 and 2, inducible nitric oxide synthase, nitrotyrosine, and vascular endothelial growth factor expression. Overall, we found that there was predominant infiltration of tumor-associated macrophages in the tumor stroma where COX-2 was robustly expressed. The other tumor-associated inflammatory markers were also mostly localized to tumor stroma. Hence, we speculate that COX-2–mediated inflammatory microenvironment may be important in WT growth and potential therapies targeting this pathway may be beneficial and should be tested in clinical settings for the treatment of WTs in children

Genome-wide loss of heterozygosity analysis ofWT1-wild-type andWT1-mutant Wilms tumors

International audienceWilms tumor (WT) is genetically heterogeneous, and the one known WT gene, WT1 at 11p13, is altered in only a subset of WTs. Previous loss of heterozygosity (LOH) analyses have revealed the existence of additional putative WT genes at 11p15, 16q, and 1p, but these analyses examined only one or a handful of chromosomes or looked at LOH at only a few markers per chromosome. We conducted a genome-wide scan for LOH in WT by using 420 markers spaced at an average of 10 cM throughout the genome and analyzed the data for two genetically defined subsets of WTs: those with mutations in WT1 and those with no detectable WT1 alteration. Our findings indicated that the incidence of LOH throughout the genome was significantly lower in our group of WTs with WT1 mutations. In WT1–wild-type tumors, we observed the expected LOH at 11p, 16q, and 1p, and, in addition, we localized a previously unobserved region of LOH at 9q. Using additional 9q markers within this region of interest, we ublocalized the region of 9q LOH to the 12.2 Mb between D9S283 and a simple tandem repeat in BAC RP11-177I8, a region containing several potential tumor-suppressor genes. As a result, we have established for the first time that WT1-mutant and WT1–wild-type WTs differ significantly in their patterns of LOH throughout the genome, suggesting that the genomic regions showing LOH in WT1–wild-type tumors harbor genes whose expression is regulated by the pleiotropic effects of WT1. Our results implicate 9q22.2–q31.1 as a region containing such a gene

Nephron Progenitor But Not Stromal Progenitor Cells Give Rise to Wilms Tumors in Mouse Models with β-Catenin Activation or Wt1 Ablation and Igf2 Upregulation

Wilms tumor, a common childhood tumor of the kidney, is thought to arise from undifferentiated renal mesenchyme. Variable tumor histology and the identification of tumor subsets displaying different gene expression profiles suggest that tumors may arise at different stages of mesenchyme differentiation and that this ontogenic variability impacts tumor pathology, biology, and clinical outcome. To test the tumorigenic potential of different cell types in the developing kidney, we used kidney progenitor-specific Cre recombinase alleles to introduce Wt1 and Ctnnb1 mutations, two alterations observed in Wilms tumor, into embryonic mouse kidney, with and without biallelic Igf2 expression, another alteration that is observed in a majority of tumors. Use of a Cre allele that targets nephron progenitors to introduce a Ctnnb1 mutation that stabilizes β-catenin resulted in the development of tumors with a predominant epithelial histology and a gene expression profile in which genes characteristic of early renal mesenchyme were not expressed. Nephron progenitors with Wt1 ablation and Igf2 biallelic expression were also tumorigenic but displayed a more triphasic histology and expressed early metanephric mesenchyme genes. In contrast, the targeting of these genetic alterations to stromal progenitors did not result in tumors. These data demonstrate that committed nephron progenitors can give rise to Wilms tumors and that committed stromal progenitors are less tumorigenic, suggesting that human Wilms tumors that display a predominantly stromal histology arise from mesenchyme before commitment to a stromal lineage