129 results on '"Huff V"'
Search Results
2. Hereditary hyperparathyroidism-jaw tumor syndrome: the endocrine tumor gene HRPT2 maps to chromosome 1q21-q31
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Szabó, J, Heath, B, Hill, V, Jackson, C, Zarbo, R, Mallette, L, Chew, S, Besser, G, Thakker, R, and Huff, V
- Abstract
The syndrome of hereditary hyperparathyroidism and jaw tumors (HPT-JT) is characterized by inheritance, in an autosomal dominant pattern, of recurrent parathyroid adenomas, fibro-osseous tumors of the mandible and/or maxilla, Wilms tumor, and parathyroid carcinoma. This syndrome is clinically and genetically distinct from other endocrine neoplasia syndromes and appears to result from mutation of an endocrine tumor gene designated "HRPT2." We studied five HPT-JT families (59 persons, 20 affected); using PCR-based markers, we instituted a genomewide linkage search after excluding several candidate genes. Lod scores were calculated at various recombination fractions (theta), penetrance 90%. We mapped HRPT2 to the long arm of chromosome 1 (1q21-q31). The maximal lod score was 6.10 at theta = .0 with marker D1S212, or > 10(6) odds in favor of linkage. In six hereditary Wilms tumor families (96 persons, 29 affected), we found no linkage to 1q markers closely linked with HRPT2 (lod scores -15.6 [D1S191] and -17.8 [D1S196], theta = .001). Nine parathyroid adenomas and one Wilms tumor from nine members of three HPT-JT families were examined for loss of heterozygosity at linked loci. The parathyroid adenomas and Wilms tumor showed no loss of heterozygosity for these DNA markers. Our data establish that HRPT2, an endocrine tumor gene on the long arm of chromosome 1, is responsible for the HPT-JT syndrome but not for the classical hereditary Wilms tumor syndrome.
- Published
- 1995
3. WT1 exon 1 deletion/insertion mutations in Wilms tumor patients, associated with di- and trinucleotide repeats and deletion hotspot consensus sequences
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Huff, V, Jaffe, N, Saunders, G F, Strong, L C, Villalba, F, and Ruteshouser, E C
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Male ,Genes, Wilms Tumor ,Base Sequence ,Chromosomes, Human, Pair 11 ,DNA Mutational Analysis ,Molecular Sequence Data ,DNA, Neoplasm ,Exons ,Minisatellite Repeats ,Wilms Tumor ,Kidney Neoplasms ,Consensus Sequence ,Humans ,Female ,Research Article ,Sequence Deletion - Abstract
The WT1 gene is known to play a role in at least some cases of Wilms tumor (WT). The first exon of the gene is highly GC rich and contains many short tandem di- and trinucleotide repeats, interrupted direct repeats, and CCTG (CAGG) motifs that have been identified as hotspots for DNA deletions. We have analyzed 80 WT patient samples for mutations in the first exon of WT1, either by SSCP analysis of the first 131 bp of the coding portion of WT1 exon 1 or by size analysis of a PCR product encompassing the coding region of exon 1 in addition to flanking noncoding regions. We report here the occurrence of somatic and germ-line deletion and insertion mutations in this portion of the gene in four WT patients. The mutations are flanked by short direct repeats, and the breakpoints are within 5 nt of a CCTG (CAGG) sequence. These data suggest that a distinctive mutational mechanism, previously unrecognized for this gene, is important for the generation of DNA mutations at the WT1 locus.
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- 1995
4. The N-body Code - A General Fortran Code for the Numerical Solution of Space Mechanics Problems on an IBN 7090 Computer
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Huff, V. N and Strack, W. C
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Meteorology - Abstract
Solution to n-body space mechanics problems via numerical integration - ibm 7090 - fortran program
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- 1963
5. THE N-BODY CODE - A GENERAL FORTRAN CODE FOR SOLUTION OF PROBLEMS IN SPACE MECHANICS BY NUMERICAL METHODS
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Dobson, W. F, Huff, V. N, and Strack, W. C
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Meteorology - Abstract
Astronomical integration code - fortran solution of space mechanics - computer program
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- 1963
6. Theoretical performance of mixtures of liquid ammonia and hydrazine as fuel with liquid fluorine as oxidant for rocket engines
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Gordon, S and Huff, V. N
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- 1953
7. Theoretical performance of liquid hydrazine and liquid fluorine as a rocket propellant
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Gordon, S and Huff, V. N
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- 1953
8. Theoretical performance of liquid ammonia and liquid fluorine as a rocket propellant
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Gordon, S and Huff, V. N
- Published
- 1953
9. Evidence for WT1 as a Wilms tumor (WT) gene: intragenic germinal deletion in bilateral WT
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Huff, V, Miwa, H, Haber, D A, Call, K M, Housman, D, Strong, L C, and Saunders, G F
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Heterozygote ,Genes, Wilms Tumor ,Chromosomes, Human, Pair 11 ,Humans ,Infant ,Female ,DNA, Neoplasm ,RNA, Neoplasm ,Chromosome Deletion ,Polymorphism, Restriction Fragment Length ,Research Article - Abstract
The inactivation of two alleles at a locus on the short arm of chromosome 11 (band 11p13) has been suggested to be critical steps in the development of Wilms tumor (WT), a childhood kidney tumor. Two similar candidate WT cDNA clones (WT33 and LK15) have recently been identified on the basis of both their expression in fetal kidney and their location within the smallest region of overlap of somatic 11p13 deletions in some tumors. These homozygous deletions, however, are large and potentially affect more than one gene. Using a cDNA probe to the candidate gene, we have analyzed DNA from both normal and tumor tissue from WT patients, in an effort to detect rearrangements at this locus. We report here a patient with bilateral WT who is heterozygous for a small (less than 11 kb) germinal deletion within this candidate gene. DNA from both tumors is homozygous for this intragenic deletion allele, which, by RNA-PRC sequence analysis, is predicted to encode a protein truncated by 180 amino acids. These data support the identification of this locus as an 11p13 WT gene (WT1) and provide direct molecular data supporting the two-hit mutational model for WT.
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- 1991
10. Transcriptional regulation of the human Wilms' tumor gene (WT1). Cell type-specific enhancer and promiscuous promoter.
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Fraizer, G.C., primary, Wu, Y.J., additional, Hewitt, S.M., additional, Maity, T., additional, Ton, C.C., additional, Huff, V., additional, and Saunders, G.F., additional
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- 1994
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11. Wilms tumor genes
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Huff, V, primary
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- 1993
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12. RNA Expression of the WT1 Gene in Wilms' Tumors in Relation to Histology
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Miwa, H., primary, Tomlinson, G. E., additional, Timmons, C. F., additional, Huff, V., additional, Cohn, S. L., additional, Strong, L. C., additional, and Saunders, G. F., additional
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- 1992
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13. An Xmnl polymorphismdetected by a humangenomic clone fromchromosomal band 11p13[D11S416]
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Weil, M.M., primary, Huff, V, additional, Compton, D.A, additional, Stronng, L.C., additional, and Saunders, G.F, additional
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- 1990
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14. A BgIII RFLP detected by the probe JA8-1 at human chromosome band 11p13 (D11S417)
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Ton, C.C.-T., primary, Huff, V., additional, Weil, M.M., additional, Strong, L.C., additional, and Saunders, G.F., additional
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- 1990
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15. Factors affecting the sensitivity of rabbit lymphoid and bone marrow cells to Streptonigrin-induced chromosome aberrations.
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Huff, V., Littlefield, L.G., DuFrain, R.J., and Wilmer, J.L.
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- 1981
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16. Pleuropulmonary blastoma: A marker for familial disease
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Priest, J.R., Watterson, J., Strong, L., Huff, V., Woods, W.G., Byrd, R.L., Friend, S.H., Newsham, I., Amylon, M.D., Pappo, A., Mahoney, D.H., Langston, C., Heyn, R., Kohut, G., Freyer, D.R., Bostrom, B., Richardson, M.S., Barredo, J., and Dehner, L.P.
- Abstract
OBJECTIVE: To catalog and evaluate patterns of disease in families of children with pleuropulmonary blastoma (PPB). METHODS: Data have been collected since 1988 on 45 children with PPB and their families. All pathologic materials were centrally reviewed. Preliminary molecular genetic analyses were performed when possible. RESULTS: In 12 of 45 patients, an association was found between PPB and other dysplasias, neoplasias, or malignancies in the patients with or in their young relatives. The diseases found to be associated with PPB include other cases of PPB, pulmonary cysts, cystic nephromas, sarcomas, medulloblastomas, thyroid dysplasias and neoplasias, malignant germ cell tumors, Hodgkin disease, leukemia, and Langerhans cell histiocytosis. Abnormalities of the p53 tumor suppressor gene, Wilms tumor suppressor gene (WT1), and the putative second genetic locus for Wilms tumor (WT2) were not found in preliminary investigations. CONCLUSIONS: The occurrence of PPB appears to herald a constitutional and heritable predisposition to dysplastic or neoplastic disease in approximately 25% of cases. All patients with PPB and their families should be investigated carefully. Further research of this new family cancer syndrome may provide insight into the genetic basis of these diseases. (J PEDIATR 1996;128:220-4)
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- 1996
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17. The carboxy-terminal 41 amino acids of herpes simplex virus type 1 glycoprotein B are not essential for production of infectious virus particles
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Huff, V, Cai, W, Glorioso, J C, and Levine, M
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Glycoprotein B (gB) is a virally encoded protein that is found in the envelope of herpes simplex virus type 1 and membranes of cells infected with herpes simplex virus type 1. It is essential for the production of infectious virus particles. An amber mutation was introduced into the gB gene by oligonucleotide-directed mutagenesis at the codon for amino acid 863 of the protein. Virus carrying this mutation should synthesize gB molecules lacking the last 41 amino acids of the cytoplasmic domain. Immunoprecipitation of infected cell extracts demonstrated the synthesis of appropriately truncated gB molecules. Characterization of the mutant virus indicated that the loss of the carboxy-terminal 41 amino acids has little effect on gB function.
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- 1988
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18. Transcriptional regulation of the human Wilms' tumor gene (WT1): Cell type-specific enhancer and promiscuous promoter
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Fraizer, G. C., Wu, Y. -J, Stephen Hewitt, Maity, T., Toni, C. C. T., Huff, V., and Saunders, G. F.
19. CHROMOSOME 11p13 ALTERATIONS IN WILMS TUMORS
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Huff, V., primary, Caroton, D. A., additional, Chao, L. -Y., additional, Schroeder, W. T., additional, Strong, L. C., additional, Saunders, G. F., additional, and Cangir, A., additional
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- 1989
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20. AnEcoRl polymorphism associated with a human genomic clone from band 11p13
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Huff, V., primary, Compton, D., additional, Lewis, W., additional, Jones, C., additional, Strong, L.C., additional, and Saunders, G.F., additional
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- 1987
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21. Factors affecting the sensitivity of rabbit lymphoid and bone marrow cells to Streptonigrin-induced chromosome aberrations
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Huff, V., primary, Littlefield, L.G., additional, DuFrain, R.J., additional, and Wilmer, J.L., additional
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- 1981
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22. Three familiar Wilms tumour families due to FWT1 — linkage and clinical analyses.
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Rahman, Nazneen, Rahman, N., Hanks, S., McDonald, M., Schwartz, C., Pritchard-Jones, K., and Huff, V.
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GENE mapping ,NEPHROBLASTOMA ,CHROMOSOMES ,LINKAGE (Genetics) - Abstract
We previously mapped a gene predisposing to familial Wilms tumor (FWT1) to chromosome 17q21, through linkage analysis of a family (MON480) with 10 cases of Wilms tumor (WT). We subsequently confirmed the FWT1 location by analyses of a second family (K1104) with 7 cases of WT. We have now analysed a third family (WTXS02) with 7 cases of WT. In this new family 6 of the 7 cases and the intervening 8 obligate carriers all share a 17q haplotype. Furthermore, analyses of 30 microsatellite markers from the FWT1 interval demonstrate that WTX502 and MON480 carry the same disease segregating haplotype and are therefore due to an FWT1 founder mutation. Review of the clinical histories of the 24 cases of WT from these three families confirms our previous phenotypic associations of FWT1 mutations. The overall mean age of 5.5 is older than the typical age of presentation of sporadic WT (3-4 years). There is also evidence of a difference in penetrance according to sex of the transmitting parent: 9 mutations were inherited paternally and the mean age at diagnosis was 9.0 years. By comparison, 15 mutations were inherited maternally and the mean age at diagnosis of these cases was 3.9 years. The Stage at presentation also differs from sporadic WT with 12 of 15 non-screen detected cases presenting at Stage 4. Our results add further evidence for a WT predisposition gene on 17q21 and indicate that the clinical presentation of FWT1 cases may differ from sporadic Wilms tumor. [ABSTRACT FROM AUTHOR]
- Published
- 2003
23. Chromosome preparations from rabbit preovulatory oocytes
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Morrison, W.D., Huff, V., Littlefield, L.G., and DuFrain, R.J.
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- 1983
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24. An EcoRl polymorphism associated with a human genomic clone from band 11p13.
- Author
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Huff, V., Compton, D., Lewis, W., Jones, C., Strong, L.C., and Saunders, G.F.
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- 1987
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25. Generation of a Wt1 conditional deletion, nuclear red fluorescent protein reporter allele in the mouse.
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Aloway JA, Ruteshouser EC, Huff V, and Behringer RR
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- Animals, Mice, Female, Genes, Reporter, Male, Gene Deletion, Red Fluorescent Protein, WT1 Proteins genetics, WT1 Proteins metabolism, Luminescent Proteins genetics, Luminescent Proteins metabolism, Alleles, Mice, Transgenic
- Abstract
A Wt1 conditional deletion, nuclear red fluorescent protein (RFP) reporter allele was generated in the mouse by gene targeting in embryonic stem cells. Upon Cre-mediated recombination, a deletion allele is generated that expresses RFP in a Wt1-specific pattern. RFP expression was detected in embryonic and adult tissues known to express Wt1, including the kidney, mesonephros, and testis. In addition, RFP expression and WT1 co-localization was detected in the adult uterine stroma and myometrium, suggesting a role in uterine function. Crosses with Wnt7a-Cre transgenic mice that express Cre in the Müllerian duct epithelium activate Wt1-directed RFP expression in the epithelium of the oviduct but not the stroma and myometrium of the uterus. This new mouse strain should be a useful resource for studies of Wt1 function and marking Wt1-expressing cells., Competing Interests: Declaration of competing interest Authors declare no competing interests., (Copyright © 2024 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.)
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- 2024
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26. The UTHealth Houston Adult Cardiovascular Genomics Certificate Program: Efficacy and Impact on Healthcare Professionals.
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Garner M, Rajani B, Vaidya P, Dayeh SA, Cecchi AC, Miyake CC, Huff V, Wanat M, Wang E, Kurzlechner LM, Landstrom AP, An D, Liang Y, Moulik M, Wong TC, Cunha SR, Cannon A, Holt RL, Milewicz DM, and Prakash SK
- Abstract
Background: The demand for genetic services has outpaced the availability of resources, challenging clinicians untrained in genetic integration into clinical decision-making. The UTHealth Adult Cardiovascular Genomics Certificate (CGC) program trains non-genetic healthcare professionals to recognize, assess, and refer patients with heritable cardiovascular diseases. This asynchronous online course includes 24 modules in three tiers of increasing complexity, using realistic clinical scenarios, interactive dialogues, quizzes, and tests to reinforce learning. We hypothesized that the CGC will increase genomic competencies in this underserved audience and encourage applying genomic concepts in clinical practice., Methods: Required course evaluations include pre- and post-assessments, knowledge checks in each module, and surveys for module-specific feedback. After 6 months, longitudinal feedback surveys gathered data on the long-term impact of the course on clinical practice and conducted focused interviews with learners., Results: The CGC was accredited in September 2022. Principal learners were nurses (24%), nurse practitioners (21%), physicians (16%), and physician assistants. Scores of 283 learners in paired pre- and post-assessments increased specific skills related to recognizing heritable diseases, understanding inheritance patterns, and interpreting genetic tests. Interviews highlighted the CGC's modular structure and linked resources as key strengths. Learners endorsed confidence to use genetic information in clinical practice, such as discussing genetic concepts and risks with patients and referring patients for genetic testing. Learners were highly likely to recommend the CGC to colleagues, citing its role in enhancing heritable disease awareness., Conclusions: The CGC program effectively empowers non-genetic clinicians to master genomic competencies, fostering collaboration to prevent deaths from heritable cardiovascular diseases, and potentially transforming healthcare education and clinical practice., Competing Interests: Authors Melyssa Garner, Bansari Rajani, Priyanka Vaidya, Samer Abu Dayeh, Alana Cecchi, Christina Miyake, Vicki Huff, Matthew Wanat, Elisabeth Wang, Leonie Kurzlechner, Andrew Landstrom, Daniel An, Yafen Liang, Mousumi Moulik, Shane Cunha, Ashley Cannon, R. Lynn Holt, Dianna Milewicz, and Siddharth Prakash declare that they have no Conflicts of interest. Timothy Wong is site principal investigator for clinical trials related to hypertrophic cardiomyopathy sponsored by Bristol Myers Squibb, Cytokinetics, and Tenaya Therapeutics and serves as an unpaid member of advisory boards for Bristol Myers Squibb and Cytokinetics.
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- 2024
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27. Hallmark discoveries in the biology of Wilms tumour.
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Perotti D, Williams RD, Wegert J, Brzezinski J, Maschietto M, Ciceri S, Gisselsson D, Gadd S, Walz AL, Furtwaengler R, Drost J, Al-Saadi R, Evageliou N, Gooskens SL, Hong AL, Murphy AJ, Ortiz MV, O'Sullivan MJ, Mullen EA, van den Heuvel-Eibrink MM, Fernandez CV, Graf N, Grundy PE, Geller JI, Dome JS, Perlman EJ, Gessler M, Huff V, and Pritchard-Jones K
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- Humans, Neoplasm Recurrence, Local, Biomarkers, Biology, Kidney Neoplasms therapy, Wilms Tumor therapy
- Abstract
The modern study of Wilms tumour was prompted nearly 50 years ago, when Alfred Knudson proposed the 'two-hit' model of tumour development. Since then, the efforts of researchers worldwide have substantially expanded our knowledge of Wilms tumour biology, including major advances in genetics - from cloning the first Wilms tumour gene to high-throughput studies that have revealed the genetic landscape of this tumour. These discoveries improve understanding of the embryonal origin of Wilms tumour, familial occurrences and associated syndromic conditions. Many efforts have been made to find and clinically apply prognostic biomarkers to Wilms tumour, for which outcomes are generally favourable, but treatment of some affected individuals remains challenging. Challenges are also posed by the intratumoural heterogeneity of biomarkers. Furthermore, preclinical models of Wilms tumour, from cell lines to organoid cultures, have evolved. Despite these many achievements, much still remains to be discovered: further molecular understanding of relapse in Wilms tumour and of the multiple origins of bilateral Wilms tumour are two examples of areas under active investigation. International collaboration, especially when large tumour series are required to obtain robust data, will help to answer some of the remaining unresolved questions., (© 2023. Springer Nature Limited.)
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- 2024
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28. Genetic and epigenetic features of bilateral Wilms tumor predisposition in patients from the Children's Oncology Group AREN18B5-Q.
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Murphy AJ, Cheng C, Williams J, Shaw TI, Pinto EM, Dieseldorff-Jones K, Brzezinski J, Renfro LA, Tornwall B, Huff V, Hong AL, Mullen EA, Crompton B, Dome JS, Fernandez CV, Geller JI, Ehrlich PF, Mulder H, Oak N, Maciezsek J, Jablonowski CM, Fleming AM, Pichavaram P, Morton CL, Easton J, Nichols KE, Clay MR, Santiago T, Zhang J, Yang J, Zambetti GP, Wang Z, Davidoff AM, and Chen X
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- Child, Humans, Genotype, DNA Methylation genetics, DNA, Epigenesis, Genetic, Genomic Imprinting, Wilms Tumor genetics, Wilms Tumor pathology, Kidney Neoplasms genetics, Kidney Neoplasms pathology
- Abstract
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., (© 2023. The Author(s).)
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- 2023
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29. The Genetic and Epigenetic Features of Bilateral Wilms Tumor Predisposition: A Report from the Children's Oncology Group AREN18B5-Q Study.
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Murphy AJ, Cheng C, Williams J, Shaw TI, Pinto EM, Dieseldorff-Jones K, Brzezinski J, Renfro LA, Tornwall B, Huff V, Hong AL, Mullen EA, Crompton B, Dome JS, Fernandez CV, Geller JI, Ehrlich PF, Mulder H, Oak N, Maciezsek J, Jablonowski C, Fleming AM, Pichavaram P, Morton CL, Easton J, Nichols KE, Clay MR, Santiago T, Zhang J, Yang J, Zambetti GP, Wang Z, Davidoff AM, and Chen X
- Abstract
This study comprehensively evaluated the landscape of genetic and epigenetic events that predispose to synchronous bilateral Wilms tumor (BWT). We performed whole exome or whole genome sequencing, total-strand RNA-seq, and DNA methylation analysis using germline and/or tumor samples from 68 patients with BWT from St. Jude Children's Research Hospital and the Children's Oncology Group. We found that 25/61 (41%) of patients evaluated harbored pathogenic or likely pathogenic germline variants, with WT1 (14.8%), NYNRIN (6.6%), TRIM28 (5%) and the BRCA-related genes (5%) BRCA1, BRCA2, and PALB2 being most common. Germline WT1 variants were strongly associated with somatic paternal uniparental disomy encompassing the 11p15.5 and 11p13/ WT1 loci and subsequent acquired pathogenic CTNNB1 variants. Somatic coding variants or genome-wide copy number alterations were almost never shared between paired synchronous BWT, suggesting that the acquisition of independent somatic variants leads to tumor formation in the context of germline or early embryonic, post-zygotic initiating events. In contrast, 11p15.5 status (loss of heterozygosity, loss or retention of imprinting) was shared among paired synchronous BWT in all but one case. The predominant molecular events for BWT predisposition include pathogenic germline variants or post-zygotic epigenetic hypermethylation at the 11p15.5 H19/ICR1 locus (loss of imprinting). This study demonstrates that post-zygotic somatic mosaicism for 11p15.5 hypermethylation/loss of imprinting is the single most common initiating molecular event predisposing to BWT. Evidence of somatic mosaicism for 11p15.5 loss of imprinting was detected in leukocytes of a cohort of BWT patients and long-term survivors, but not in unilateral Wilms tumor patients and long-term survivors or controls, further supporting the hypothesis that post-zygotic 11p15.5 alterations occurred in the mesoderm of patients who go on to develop BWT. Due to the preponderance of BWT patients with demonstrable germline or early embryonic tumor predisposition, BWT exhibits a unique biology when compared to unilateral Wilms tumor and therefore warrants continued refinement of its own treatment-relevant biomarkers which in turn may inform directed treatment strategies in the future., Competing Interests: Conflict of Interest Statement: The authors have no conflicts of interest to declare.
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- 2023
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30. Genetic changes associated with relapse in favorable histology Wilms tumor: A Children's Oncology Group AREN03B2 study.
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Gadd S, Huff V, Skol AD, Renfro LA, Fernandez CV, Mullen EA, Jones CD, Hoadley KA, Yap KL, Ramirez NC, Aris S, Phung QH, and Perlman EJ
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- Child, Genes, Wilms Tumor, Homeodomain Proteins genetics, Humans, N-Myc Proto-Oncogene Protein genetics, Neoplasm Recurrence, Local genetics, Kidney Neoplasms genetics, Wilms Tumor genetics
- Abstract
Over the last decade, sequencing of primary tumors has clarified the genetic underpinnings of Wilms tumor but has not affected therapy, outcome, or toxicity. We now sharpen our focus on relapse samples from the umbrella AREN03B2 study. We show that over 40% of relapse samples contain mutations in SIX1 or genes of the MYCN network, drivers of progenitor proliferation. Not previously seen in large studies of primary Wilms tumors, DIS3 and TERT are now identified as recurrently mutated. The analysis of primary-relapse tumor pairs suggests that 11p15 loss of heterozygosity (and other copy number changes) and mutations in WT1 and MLLT1 typically occur early, but mutations in SIX1, MYCN, and WTX are late developments in some individuals. Most strikingly, 75% of relapse samples had gain of 1q, providing strong conceptual support for studying circulating tumor DNA in clinical trials to better detect 1q gain earlier and monitor response., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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31. Wilm's tumor 1 promotes memory flexibility.
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Mariottini C, Munari L, Gunzel E, Seco JM, Tzavaras N, Hansen J, Stern SA, Gao V, Aleyasin H, Sharma A, Azeloglu EU, Hodes GE, Russo SJ, Huff V, Birtwistle MR, Blitzer RD, Alberini CM, and Iyengar R
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- Animals, Behavior, Animal physiology, CA1 Region, Hippocampal metabolism, Fear physiology, Long-Term Potentiation physiology, Male, Memory Disorders pathology, Mice, Mice, Knockout, Neuronal Plasticity physiology, Neurons physiology, Rats, Rats, Sprague-Dawley, Repressor Proteins genetics, WT1 Proteins, Hippocampus physiology, Memory physiology, Repressor Proteins metabolism
- Abstract
Under physiological conditions, strength and persistence of memory must be regulated in order to produce behavioral flexibility. In fact, impairments in memory flexibility are associated with pathologies such as post-traumatic stress disorder or autism; however, the underlying mechanisms that enable memory flexibility are still poorly understood. Here, we identify transcriptional repressor Wilm's Tumor 1 (WT1) as a critical synaptic plasticity regulator that decreases memory strength, promoting memory flexibility. WT1 is activated in the hippocampus following induction of long-term potentiation (LTP) or learning. WT1 knockdown enhances CA1 neuronal excitability, LTP and long-term memory whereas its overexpression weakens memory retention. Moreover, forebrain WT1-deficient mice show deficits in both reversal, sequential learning tasks and contextual fear extinction, exhibiting impaired memory flexibility. We conclude that WT1 limits memory strength or promotes memory weakening, thus enabling memory flexibility, a process that is critical for learning from new experiences.
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- 2019
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32. A unique subset of low-risk Wilms tumors is characterized by loss of function of TRIM28 (KAP1), a gene critical in early renal development: A Children's Oncology Group study.
- Author
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Armstrong AE, Gadd S, Huff V, Gerhard DS, Dome JS, and Perlman EJ
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- Anaplasia genetics, Anaplasia pathology, DNA Methylation genetics, Female, Germ-Line Mutation genetics, HEK293 Cells, Humans, Infant, Infant, Newborn, Kidney growth & development, Kidney metabolism, Kidney pathology, Kidney Neoplasms pathology, Loss of Function Mutation genetics, Male, Risk Factors, Wilms Tumor pathology, Carcinogenesis genetics, Kidney Neoplasms genetics, Tripartite Motif-Containing Protein 28 genetics, Wilms Tumor genetics
- Abstract
This study explores the genomic alterations that contribute to the formation of a unique subset of low-risk, epithelial differentiated, favorable histology Wilms tumors (WT), tumors that have been characterized by their expression of post-induction renal developmental genes (Subset 1 WT). We demonstrate copy neutral loss of heterozygosity involving 19q13.32-q13.43, unaccompanied by evidence for imprinting by DNA methylation. We further identified loss-of-function somatic mutations in TRIM28 (also known as KAP1), located at 19q13, in 8/9 Subset 1 tumors analyzed. An additional germline TRIM28 mutation was identified in one patient. Retrospective evaluation of previously analyzed WT outside of Subset 1 identified an additional tumor with anaplasia and both TRIM28 and TP53 mutations. A major function of TRIM28 is the repression of endogenous retroviruses early in development. We depleted TRIM28 in HEK293 cells, which resulted in increased expression of endogenous retroviruses, a finding also demonstrated in TRIM28-mutant WT. TRIM28 has been shown by others to be active during early renal development, and to interact with WTX, another gene recurrently mutated in WT. Our findings suggest that inactivation of TRIM28 early in renal development contributes to the formation of this unique subset of FHWTs, although the precise manner in which TRIM28 impacts both normal renal development and oncogenesis remains elusive., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2018
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33. Knock-in of the Wt1 R394W mutation causes MDS and cooperates with Flt3/ITD to drive aggressive myeloid neoplasms in mice.
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Annesley CE, Rabik C, Duffield AS, Rau RE, Magoon D, Li L, Huff V, Small D, Loeb DM, and Brown P
- Abstract
Wilms tumor 1 (WT1) is a zinc finger transcriptional regulator, and has been implicated as both a tumor suppressor and oncogene in various malignancies. Mutations in the DNA-binding domain of the WT1 gene are described in 10-15% of normal-karyotype AML (NK-AML) in pediatric and adult patients. Similar WT1 mutations have been reported in adult patients with myelodysplastic syndrome (MDS). WT1 mutations have been independently associated with treatment failure and poor prognosis in NK-AML. Internal tandem duplication (ITD) mutations of FMS-like tyrosine kinase 3 ( FLT3 ) commonly co-occur with WT1 -mutant AML, suggesting a cooperative role in leukemogenesis. The functional role of WT1 mutations in hematologic malignancies appears to be complex and is not yet fully elucidated. Here, we describe the hematologic phenotype of a knock-in mouse model of a Wt1 mutation (R394W), described in cases of human leukemia. We show that Wt1
+/R394W mice develop MDS which becomes 100% penetrant in a transplant model, exhibit an aberrant expansion of myeloid progenitor cells, and demonstrate enhanced self-renewal of hematopoietic progenitor cells in vitro . We crossbred Wt1+/R394W mice with knock-in Flt3+/ITD mice, and show that mice with both mutations ( Flt3+/ITD / Wt1+/R394W ) develop a transplantable MDS/MPN, with more aggressive features compared to either single mutant mouse model., Competing Interests: CONFLICTS OF INTEREST V.H. has ownership interest in Codified Genomics, LLC. The remaining authors declare no competing financial interests.- Published
- 2018
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34. A Children's Oncology Group and TARGET initiative exploring the genetic landscape of Wilms tumor.
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Gadd S, Huff V, Walz AL, Ooms AHAG, Armstrong AE, Gerhard DS, Smith MA, Auvil JMG, Meerzaman D, Chen QR, Hsu CH, Yan C, Nguyen C, Hu Y, Hermida LC, Davidsen T, Gesuwan P, Ma Y, Zong Z, Mungall AJ, Moore RA, Marra MA, Dome JS, Mullighan CG, Ma J, Wheeler DA, Hampton OA, Ross N, Gastier-Foster JM, Arold ST, and Perlman EJ
- Subjects
- Aneuploidy, DNA Methylation, Epigenesis, Genetic, Gene Dosage, Gene Expression Regulation, Neoplastic, Genome-Wide Association Study, Germ-Line Mutation, Humans, MicroRNAs biosynthesis, MicroRNAs genetics, Protein Conformation, RNA, Messenger biosynthesis, RNA, Messenger genetics, RNA, Neoplasm biosynthesis, RNA, Neoplasm genetics, Genes, Neoplasm, Kidney Neoplasms genetics, Wilms Tumor genetics
- Abstract
We performed genome-wide sequencing and analyzed mRNA and miRNA expression, DNA copy number, and DNA methylation in 117 Wilms tumors, followed by targeted sequencing of 651 Wilms tumors. In addition to genes previously implicated in Wilms tumors (WT1, CTNNB1, AMER1, DROSHA, DGCR8, XPO5, DICER1, SIX1, SIX2, MLLT1, MYCN, and TP53), we identified mutations in genes not previously recognized as recurrently involved in Wilms tumors, the most frequent being BCOR, BCORL1, NONO, MAX, COL6A3, ASXL1, MAP3K4, and ARID1A. DNA copy number changes resulted in recurrent 1q gain, MYCN amplification, LIN28B gain, and MIRLET7A loss. Unexpected germline variants involved PALB2 and CHEK2. Integrated analyses support two major classes of genetic changes that preserve the progenitor state and/or interrupt normal development.
- Published
- 2017
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35. Clinical Outcome and Biological Predictors of Relapse After Nephrectomy Only for Very Low-risk Wilms Tumor: A Report From Children's Oncology Group AREN0532.
- Author
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Fernandez CV, Perlman EJ, Mullen EA, Chi YY, Hamilton TE, Gow KW, Ferrer FA, Barnhart DC, Ehrlich PF, Khanna G, Kalapurakal JA, Bocking T, Huff V, Tian J, Geller JI, Grundy PE, Anderson JR, Dome JS, and Shamberger RC
- Subjects
- Age Distribution, Biomarkers, Tumor analysis, Child, Child, Preschool, Cohort Studies, Disease-Free Survival, Female, Follow-Up Studies, Humans, Incidence, Kidney Neoplasms mortality, Kidney Neoplasms pathology, Male, Neoplasm Invasiveness pathology, Neoplasm Recurrence, Local pathology, Neoplasm Staging, Nephrectomy mortality, Retrospective Studies, Risk Assessment, Sex Distribution, Survival Analysis, Wilms Tumor mortality, Wilms Tumor pathology, Biomarkers, Tumor genetics, Kidney Neoplasms surgery, Neoplasm Recurrence, Local epidemiology, Nephrectomy methods, Watchful Waiting methods, Wilms Tumor surgery
- Abstract
Objective: To determine if observation alone after nephrectomy in very low-risk Wilms tumor (defined as stage I favorable histology Wilms tumors with nephrectomy weight <550g and age at diagnosis <2 years) results in satisfactory event-free survival and overall survival, and to correlate relapse with biomarkers., Patients and Methods: The AREN0532 study enrolled patients with very low-risk Wilms tumor confirmed by central review of pathology, diagnostic imaging, and surgical reports. After nephrectomy, patients were followed without adjuvant chemotherapy. Evaluable tumors were analyzed for WT1mutation, 1p and 16q copy loss, 1q copy gain, and 11p15 imprinting. The study was powered to detect a reduction in 4-year EFS from 87% to 75% and overall survival from 95% to 88%., Results: A total of 116 eligible patients enrolled with a median follow up of 80 months (range: 5-97 months). Twelve patients relapsed. Estimated 4-year event-free survival was 89.7% (95% confidence interval 84.1-95.2%) and overall survival was 100%. First sites of relapse were lung (n = 5), tumor bed (n = 4), and abdomen (n = 2), with one metachronous tumor in the contralateral kidney (n = 1) at a median time of 4.3 months for those who relapsed (range 2.3-44 months). The presence of intralobar (P = 0.46) or perilobar rests (P = 1.0) were not associated with relapse (P = 0.16). 1q gain, 1p and 16q loss, and WT1 mutation status were not associated with relapse. 11p15 methylation status was associated relapse (20% relapse with loss of heterozygosity, 25% with loss of imprinting, and 3.3% relapse with retention of the normal imprinting (P = 0.011))., Conclusions: Most patients meeting very low-risk criteria can be safely managed by nephrectomy alone with resultant reduced exposure to chemotherapy. Expansion of an observation alone strategy for low-risk Wilms tumor incorporating both clinical features and biomarkers should be considered.
- Published
- 2017
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36. Wt1 directs the lineage specification of sertoli and granulosa cells by repressing Sf1 expression.
- Author
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Chen M, Zhang L, Cui X, Lin X, Li Y, Wang Y, Wang Y, Qin Y, Chen D, Han C, Zhou B, Huff V, and Gao F
- Subjects
- Animals, Cell Differentiation genetics, Cells, Cultured, Down-Regulation genetics, Embryo, Mammalian, Female, Gene Expression Regulation, Developmental, Granulosa Cells metabolism, Male, Mice, Mice, Transgenic, Pregnancy, Sertoli Cells metabolism, Sex Determination Processes genetics, WT1 Proteins, Cell Lineage genetics, Granulosa Cells physiology, RNA Splicing Factors genetics, Repressor Proteins physiology, Sertoli Cells physiology, Sex Differentiation genetics
- Abstract
Supporting cells (Sertoli and granulosa) and steroidogenic cells (Leydig and theca-interstitium) are two major somatic cell types in mammalian gonads, but the mechanisms that control their differentiation during gonad development remain elusive. In this study, we found that deletion of Wt1 in the ovary after sex determination caused ectopic development of steroidogenic cells at the embryonic stage. Furthermore, differentiation of both Sertoli and granulosa cells was blocked when Wt1 was deleted before sex determination and most genital ridge somatic cells differentiated into steroidogenic cells in both male and female gonads. Further studies revealed that WT1 repressed Sf1 expression by directly binding to the Sf1 promoter region, and the repressive function was completely abolished when WT1 binding sites were mutated. This study demonstrates that Wt1 is required for the lineage specification of both Sertoli and granulosa cells by repressing Sf1 expression. Without Wt1, the expression of Sf1 was upregulated and the somatic cells differentiated into steroidogenic cells instead of supporting cells. Our study uncovers a novel mechanism of somatic cell differentiation during gonad development., (© 2017. Published by The Company of Biologists Ltd.)
- Published
- 2017
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37. Significance of TP53 Mutation in Wilms Tumors with Diffuse Anaplasia: A Report from the Children's Oncology Group.
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Ooms AH, Gadd S, Gerhard DS, Smith MA, Guidry Auvil JM, Meerzaman D, Chen QR, Hsu CH, Yan C, Nguyen C, Hu Y, Ma Y, Zong Z, Mungall AJ, Moore RA, Marra MA, Huff V, Dome JS, Chi YY, Tian J, Geller JI, Mullighan CG, Ma J, Wheeler DA, Hampton OA, Walz AL, van den Heuvel-Eibrink MM, de Krijger RR, Ross N, Gastier-Foster JM, and Perlman EJ
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Child, Female, Gene Expression genetics, Humans, Immunohistochemistry methods, Male, Middle Aged, Retrospective Studies, Young Adult, Anaplasia genetics, Kidney Neoplasms genetics, Mutation genetics, Radius abnormalities, Tumor Suppressor Protein p53 genetics, Wilms Tumor genetics
- Abstract
Purpose: To investigate the role and significance of TP53 mutation in diffusely anaplastic Wilms tumors (DAWTs)., Experimental Design: All DAWTs registered on National Wilms Tumor Study-5 (n = 118) with available samples were analyzed for TP53 mutations and copy loss. Integrative genomic analysis was performed on 39 selected DAWTs., Results: Following analysis of a single random sample, 57 DAWTs (48%) demonstrated TP53 mutations, 13 (11%) copy loss without mutation, and 48 (41%) lacked both [defined as TP53-wild-type (wt)]. Patients with stage III/IV TP53-wt DAWTs (but not those with stage I/II disease) had significantly lower relapse and death rates than those with TP53 abnormalities. In-depth analysis of a subset of 39 DAWTs showed seven (18%) to be TP53-wt: These demonstrated gene expression evidence of an active p53 pathway. Retrospective pathology review of TP53-wt DAWT revealed no or very low volume of anaplasia in six of seven tumors. When samples from TP53-wt tumors known to contain anaplasia histologically were available, abnormal p53 protein accumulation was observed by immunohistochemistry., Conclusions: These data support the key role of TP53 loss in the development of anaplasia in WT, and support its significant clinical impact in patients with residual anaplastic tumor following surgery. These data also suggest that most DAWTs will show evidence of TP53 mutation when samples selected for the presence of anaplasia are analyzed. This suggests that modifications of the current criteria to also consider volume of anaplasia and documentation of TP53 aberrations may better reflect the risk of relapse and death and enable optimization of therapeutic stratification. Clin Cancer Res; 22(22); 5582-91. ©2016 AACR., Competing Interests: The authors disclose no potential conflicts of interest, (©2016 American Association for Cancer Research.)
- Published
- 2016
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38. Identification of germline DICER1 mutations and loss of heterozygosity in familial Wilms tumour.
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Palculict TB, Ruteshouser EC, Fan Y, Wang W, Strong L, and Huff V
- Subjects
- Adolescent, Adult, Child, Preschool, Female, Genetic Predisposition to Disease genetics, Heterozygote, Humans, Male, Middle Aged, Pedigree, DEAD-box RNA Helicases genetics, Germ-Line Mutation genetics, Loss of Heterozygosity genetics, Ribonuclease III genetics, Wilms Tumor genetics
- Abstract
Wilms tumour (WT), a paediatric renal cancer, is the most common childhood kidney cancer. The aetiology of WT is heterogeneous with multiple genes known to result in WT tumorigenesis. However, these genes are rarely associated with familial Wilms tumour (FWT). To identify mutations predisposing to FWT, we performed whole-genome sequencing using genomic DNA from three affected/obligate carriers in a large WT family, followed by Sanger sequencing of candidate gene mutations in 47 additional WT families to determine their frequency in FWT. As a result, we identified two novel germline DICER1 mutations (G803R and R800Xfs5) co-segregating in two families, thus expanding the number of reported WT families with unique germline DICER1 mutations. The one large family was found to include individuals with multiple DICER1 syndrome phenotypes, including four WT cases. Interestingly, carriers of the DICER1 mutation displayed a greatly increased frequency of WT development compared with the penetrance observed in previously published pedigrees. Also uniquely, in one tumour this DICER1 mutant allele (G803R) was reduced to homozygosity in contrast to the somatic hotspot mutations typically observed in tumours in DICER1 families., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)
- Published
- 2016
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39. 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.
- Author
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Huang L, Mokkapati S, Hu Q, Ruteshouser EC, Hicks MJ, and Huff V
- Subjects
- Animals, Cell Line, Tumor, Disease Models, Animal, Gene Expression Regulation, Neoplastic, Humans, Integrases genetics, Kidney Neoplasms pathology, Mice, Mutation, Nephrons metabolism, Nephrons pathology, Stromal Cells metabolism, Transcriptional Activation genetics, WT1 Proteins, Wilms Tumor pathology, Insulin-Like Growth Factor II genetics, Kidney Neoplasms genetics, Repressor Proteins genetics, Wilms Tumor genetics, beta Catenin genetics
- Abstract
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., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
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40. MLLT1 YEATS domain mutations in clinically distinctive Favourable Histology Wilms tumours.
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Perlman EJ, Gadd S, Arold ST, Radhakrishnan A, Gerhard DS, Jennings L, Huff V, Guidry Auvil JM, Davidsen TM, Dome JS, Meerzaman D, Hsu CH, Nguyen C, Anderson J, Ma Y, Mungall AJ, Moore RA, Marra MA, Mullighan CG, Ma J, Wheeler DA, Hampton OA, Gastier-Foster JM, Ross N, and Smith MA
- Subjects
- Cohort Studies, Histones genetics, Histones metabolism, Humans, Kidney metabolism, Kidney Neoplasms metabolism, Mutation, Neoplasm Proteins chemistry, Neoplasm Proteins metabolism, Nuclear Proteins chemistry, Nuclear Proteins metabolism, Protein Binding, Protein Structure, Tertiary, Proto-Oncogene Proteins c-myc genetics, Proto-Oncogene Proteins c-myc metabolism, Transcription Factors chemistry, Transcription Factors metabolism, Wilms Tumor metabolism, Kidney Neoplasms genetics, Neoplasm Proteins genetics, Nuclear Proteins genetics, Transcription Factors genetics, Wilms Tumor genetics
- Abstract
Wilms tumour is an embryonal tumour of childhood that closely resembles the developing kidney. Genomic changes responsible for the development of the majority of Wilms tumours remain largely unknown. Here we identify recurrent mutations within Wilms tumours that involve the highly conserved YEATS domain of MLLT1 (ENL), a gene known to be involved in transcriptional elongation during early development. The mutant MLLT1 protein shows altered binding to acetylated histone tails. Moreover, MLLT1-mutant tumours show an increase in MYC gene expression and HOX dysregulation. Patients with MLLT1-mutant tumours present at a younger age and have a high prevalence of precursor intralobar nephrogenic rests. These data support a model whereby activating MLLT1 mutations early in renal development result in the development of Wilms tumour.
- Published
- 2015
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41. Reprogramming of Sertoli cells to fetal-like Leydig cells by Wt1 ablation.
- Author
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Zhang L, Chen M, Wen Q, Li Y, Wang Y, Wang Y, Qin Y, Cui X, Yang L, Huff V, and Gao F
- Subjects
- Animals, Cell Differentiation, Cell Lineage, Gene Deletion, Immunohistochemistry, Male, Mice, Knockout, Testis embryology, beta Catenin genetics, Gene Expression Regulation, Developmental, Leydig Cells cytology, Sertoli Cells cytology, Testis growth & development, WT1 Proteins metabolism
- Abstract
Sertoli and Leydig cells, the two major somatic cell types in the testis, have different morphologies and functions. Both are essential for gonad development and spermatogenesis. However, whether these cells are derived from the same progenitor cells and the mechanism regulating the differentiation between these two cell types during gonad development remains unclear. A previous study showed that overactivation of Ctnnb1 (cadherin-associated protein, beta 1) in Sertoli cells resulted in Sertoli cell tumors. Surprisingly, in the present study, we found that simultaneous deletion of Wilms' Tumor Gene 1 (Wt1) and overactivation of Ctnnb1 in Sertoli cells led to Leydig cell-like tumor development. Lineage tracing experiments revealed that the Leydig-like tumor cells were derived from Sertoli cells. Further studies confirmed that Wt1 is required for the maintenance of the Sertoli cell lineage and that deletion of Wt1 resulted in the reprogramming of Sertoli cells to Leydig cells. Consistent with this interpretation, overexpression of Wt1 in Leydig cells led to the up-regulation of Sertoli cell-specific gene expression and the down-regulation of steroidogenic gene expression. These results demonstrate that the distinction between Sertoli cells and Leydig cells is regulated by Wt1, implying that these two cell types most likely originate from the same progenitor cells. This study thus provides a novel concept for somatic cell fate determination in testis development that may also represent an etiology of male infertility in human patients.
- Published
- 2015
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42. Recurrent DGCR8, DROSHA, and SIX homeodomain mutations in favorable histology Wilms tumors.
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Walz AL, Ooms A, Gadd S, Gerhard DS, Smith MA, Guidry Auvil JM, Meerzaman D, Chen QR, Hsu CH, Yan C, Nguyen C, Hu Y, Bowlby R, Brooks D, Ma Y, Mungall AJ, Moore RA, Schein J, Marra MA, Huff V, Dome JS, Chi YY, Mullighan CG, Ma J, Wheeler DA, Hampton OA, Jafari N, Ross N, Gastier-Foster JM, and Perlman EJ
- Subjects
- Gene Expression Regulation, Neoplastic, Humans, Loss of Heterozygosity genetics, MicroRNAs genetics, Mutation, Neoplasm Recurrence, Local genetics, Neoplasm Recurrence, Local pathology, Polymorphism, Single Nucleotide, Wilms Tumor pathology, Homeodomain Proteins genetics, Nerve Tissue Proteins genetics, RNA-Binding Proteins genetics, Ribonuclease III genetics, Wilms Tumor genetics
- Abstract
We report the most common single-nucleotide substitution/deletion mutations in favorable histology Wilms tumors (FHWTs) to occur within SIX1/2 (7% of 534 tumors) and microRNA processing genes (miRNAPGs) DGCR8 and DROSHA (15% of 534 tumors). Comprehensive analysis of 77 FHWTs indicates that tumors with SIX1/2 and/or miRNAPG mutations show a pre-induction metanephric mesenchyme gene expression pattern and are significantly associated with both perilobar nephrogenic rests and 11p15 imprinting aberrations. Significantly decreased expression of mature Let-7a and the miR-200 family (responsible for mesenchymal-to-epithelial transition) in miRNAPG mutant tumors is associated with an undifferentiated blastemal histology. The combination of SIX and miRNAPG mutations in the same tumor is associated with evidence of RAS activation and a higher rate of relapse and death., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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43. β-catenin activation in a novel liver progenitor cell type is sufficient to cause hepatocellular carcinoma and hepatoblastoma.
- Author
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Mokkapati S, Niopek K, Huang L, Cunniff KJ, Ruteshouser EC, deCaestecker M, Finegold MJ, and Huff V
- Subjects
- Animals, Cell Growth Processes physiology, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Liver Neoplasms, Experimental genetics, Liver Neoplasms, Experimental pathology, Mice, Mice, Transgenic, Neoplastic Stem Cells pathology, Signal Transduction, Liver Neoplasms, Experimental metabolism, Neoplastic Stem Cells metabolism, Wnt Proteins metabolism
- Abstract
Hepatocellular carcinoma (HCC) was thought historically to arise from hepatocytes, but gene expression studies have suggested that it can also arise from fetal progenitor cells or their adult progenitor progeny. Here, we report the identification of a unique population of fetal liver progenitor cells in mice that can serve as a cell of origin in HCC development. In the transgenic model used, mice carry the Cited1-CreER(TM)-GFP BAC transgene in which a tamoxifen-inducible Cre (CreER(TM)) and GFP are controlled by a 190-kb 5' genomic region of Cited1, a transcriptional coactivator protein for CBP/p300. Wnt signaling is critical for regulating self-renewal of progenitor/stem cells and has been implicated in the etiology of cancers of rapidly self-renewing tissues, so we hypothesized that Wnt pathway activation in CreER(TM)-GFP(+) progenitors would result in HCC. In livers from the mouse model, transgene-expressing cells represented 4% of liver cells at E11.5 when other markers were expressed, characteristic of the hepatic stem/progenitor cells that give rise to adult hepatocytes, cholangiocytes, and SOX9(+) periductal cells. By 26 weeks of age, more than 90% of Cited1-CreER(TM)-GFP;Ctnnb1(ex3(fl)) mice with Wnt pathway activation developed HCC and, in some cases, hepatoblastomas and lung metastases. HCC and hepatoblastomas resembled their human counterparts histologically, showing activation of Wnt, Ras/Raf/MAPK, and PI3K/AKT/mTOR pathways and expressing relevant stem/progenitor cell markers. Our results show that Wnt pathway activation is sufficient for malignant transformation of these unique liver progenitor cells, offering functional support for a fetal/adult progenitor origin of some human HCC. We believe this model may offer a valuable new tool to improve understanding of the cellular etiology and biology of HCC and hepatoblastomas and the development of improved therapeutics for these diseases., (©2014 American Association for Cancer Research.)
- Published
- 2014
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44. Characterization of the inflammatory microenvironment and identification of potential therapeutic targets in wilms tumors.
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Maturu P, Overwijk WW, Hicks J, Ekmekcioglu S, Grimm EA, and Huff V
- Abstract
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., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2014
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45. Wilms' tumor blastemal stem cells dedifferentiate to propagate the tumor bulk.
- Author
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Shukrun R, Pode-Shakked N, Pleniceanu O, Omer D, Vax E, Peer E, Pri-Chen S, Jacob J, Hu Q, Harari-Steinberg O, Huff V, and Dekel B
- Subjects
- Aldehyde Dehydrogenase 1 Family, Animals, CD56 Antigen metabolism, Cell Differentiation genetics, Cell Differentiation physiology, Female, Humans, Isoenzymes metabolism, Kidney Neoplasms metabolism, Kidney Neoplasms pathology, Mice, Mice, SCID, Models, Biological, Neoplastic Stem Cells metabolism, Retinal Dehydrogenase metabolism, Neoplastic Stem Cells pathology, Wilms Tumor metabolism, Wilms Tumor pathology
- Abstract
An open question remains in cancer stem cell (CSC) biology whether CSCs are by definition at the top of the differentiation hierarchy of the tumor. Wilms' tumor (WT), composed of blastema and differentiated renal elements resembling the nephrogenic zone of the developing kidney, is a valuable model for studying this question because early kidney differentiation is well characterized. WT neural cell adhesion molecule 1-positive (NCAM1(+)) aldehyde dehydrogenase 1-positive (ALDH1(+)) CSCs have been recently isolated and shown to harbor early renal progenitor traits. Herein, by generating pure blastema WT xenografts, composed solely of cells expressing the renal developmental markers SIX2 and NCAM1, we surprisingly show that sorted ALDH1(+) WT CSCs do not correspond to earliest renal stem cells. Rather, gene expression and proteomic comparative analyses disclose a cell type skewed more toward epithelial differentiation than the bulk of the blastema. Thus, WT CSCs are likely to dedifferentiate to propagate WT blastema.
- Published
- 2014
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46. Race disparities in peptide profiles of North American and Kenyan Wilms tumor specimens.
- Author
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Libes JM, Seeley EH, Li M, Axt JR, Pierce J, Correa H, Newton M, Hansen E, Judd A, McDonald H, Caprioli RM, Naranjo A, Huff V, O'Neill JA Jr, and Lovvorn HN 3rd
- Subjects
- Algorithms, Child, Child, Preschool, Cluster Analysis, Female, Humans, Kenya, Kidney Neoplasms metabolism, Male, Principal Component Analysis, Proteomics, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, United States, Wilms Tumor metabolism, Black or African American, Biomarkers, Tumor metabolism, Black People, Health Status Disparities, Kidney Neoplasms ethnology, Proteome metabolism, White People, Wilms Tumor ethnology
- Abstract
Background: Wilms tumor (WT) is the most common childhood kidney cancer worldwide and arises in children of black African ancestry with greater frequency and severity than other race groups. A biologic basis for this pediatric cancer disparity has not been previously determined. We hypothesized that unique molecular fingerprints might underlie the variable incidence and distinct disease characteristics of WT observed between race groups., Study Design: To evaluate molecular disparities between WTs of different race groups, the Children's Oncology Group provided 80 favorable histology specimens divided evenly between black and white patients and matched for disease characteristics. As a surrogate of black sub-Saharan African patients, we also analyzed 18 Kenyan WT specimens. Tissues were probed for peptide profiles using matrix-assisted laser desorption ionization time of flight imaging mass spectrometry. To control for histologic variability within and between specimens, cellular regions were analyzed separately as triphasic (containing blastema, epithelia, and stroma), blastema only, and stroma only. Data were queried using ClinProTools and statistically analyzed., Results: Peptide profiles, detected in triphasic WT regions, recognized race with good accuracy, which increased for blastema- or stroma-only regions. Peptide profiles from North American WTs differed between black and white race groups but were far more similar in composition than Kenyan specimens. Individual peptides were identified that also associated with WT patient and disease characteristics (eg, treatment failure and stage). Statistically significant peptide fragments were used to sequence proteins, revealing specific cellular signaling pathways and candidate drug targets., Conclusions: Wilms tumor specimens arising among different race groups show unique molecular fingerprints that could explain disparate incidences and biologic behavior and that could reveal novel therapeutic targets., (Copyright © 2014 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)
- Published
- 2014
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47. Wt1 functions in ovarian follicle development by regulating granulosa cell differentiation.
- Author
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Gao F, Zhang J, Wang X, Yang J, Chen D, Huff V, and Liu YX
- Subjects
- 3-Hydroxysteroid Dehydrogenases metabolism, Adaptor Proteins, Signal Transducing metabolism, Animals, Aromatase metabolism, Cadherins metabolism, Cell Differentiation, Cell Polarity, Female, Fertility, Gene Expression Regulation, Granulosa Cells pathology, Humans, Male, Mice, Ovarian Follicle pathology, Ovulation, Pregnancy, Primary Ovarian Insufficiency pathology, Receptors, FSH metabolism, WT1 Proteins genetics, Granulosa Cells cytology, Granulosa Cells metabolism, Ovarian Follicle physiology, WT1 Proteins physiology
- Abstract
The Wt1 gene encodes a nuclear transcription factor that is specifically expressed in ovarian granulosa cells. However, the physiological significance of Wt1 in ovarian follicle development remains elusive. In this study, we found that Wt1(+/R394W) mice were grossly normal, however, the females displayed severe reproductive defects. Only ∼15% of the Wt1(+/R394W) females became pregnant after mating with wild-type males, compared with 88.2% of control females. Further study revealed that the subfertility of Wt1(+/R394W) females was caused by aberrant ovarian follicle development. Compared with control females, the ovary size and the number of developing follicles was significantly decreased in Wt1 mutant ovaries which was very similar to premature ovarian failure (POF) in human patients. The results of in vitro studies demonstrated that the expression of follicle stimulating hormone receptor (FSHR), 3β-hydroxysteroid dehydrogenase and Aromatase was inhibited by Wt1 in granulosa cells, and mutation of Wt1 resulted in the upregulation of these genes and in the premature differentiation of granulosa cells. We also found that Wt1 was likely involved in granulosa cell development via the regulation of E-cadherin and Par6b expression. Mutation in Wt1 caused defects in polarity establishment in granulosa cells, which also likely contributed to the observed aberrant follicle development. The results of this study provide new mechanisms for understanding the regulation of ovarian follicle development and potential pathological cause of POF in human patients.
- Published
- 2014
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48. Children's Oncology Group's 2013 blueprint for research: renal tumors.
- Author
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Dome JS, Fernandez CV, Mullen EA, Kalapurakal JA, Geller JI, Huff V, Gratias EJ, Dix DB, Ehrlich PF, Khanna G, Malogolowkin MH, Anderson JR, Naranjo A, and Perlman EJ
- Subjects
- Chemotherapy, Adjuvant, Child, Humans, Nephrectomy, Research, Clinical Trials as Topic, Kidney Neoplasms genetics, Kidney Neoplasms pathology, Kidney Neoplasms therapy
- Abstract
Renal malignancies are among the most prevalent pediatric cancers. The most common is favorable histology Wilms tumor (FHWT), which has 5-year overall survival exceeding 90%. Other pediatric renal malignancies, including anaplastic Wilms tumor, clear cell sarcoma, malignant rhabdoid tumor, and renal cell carcinoma, have less favorable outcomes. Recent clinical trials have identified gain of chromosome 1q as a prognostic marker for FHWT. Upcoming studies will evaluate therapy adjustments based on this and other novel biomarkers. For high-risk renal tumors, new treatment regimens will incorporate biological therapies. A research blueprint, viewed from the perspective of the Children's Oncology Group, is presented., (Copyright © 2012 Wiley Periodicals, Inc.)
- Published
- 2013
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49. Left-sided cryptorchidism in mice with Wilms' tumour 1 gene deletion in gubernaculum testis.
- Author
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Kaftanovskaya EM, Neukirchner G, Huff V, and Agoulnik AI
- Subjects
- Animals, Animals, Newborn, Female, Flow Cytometry, Gene Deletion, Inguinal Canal growth & development, Inguinal Canal physiology, Kidney growth & development, Kidney physiology, Lac Operon, Male, Mice, Mice, Knockout, Receptors, Androgen genetics, Testis growth & development, Cryptorchidism genetics, Gene Expression Regulation, Developmental physiology, Testis abnormalities, Testis physiology, WT1 Proteins genetics
- Abstract
A significant number of patients with germline mutations in the Wilms' tumour 1 (WT1) gene, a transcriptional factor essential for early renal and gonadal development, display cryptorchidism or non-scrotal testis position. We show here that WT1 is expressed during development in the mouse gubernacular ligament connecting the testis to the abdominal wall. Conditional inactivation of Wt1 in the gubernaculum (GU-WT1KO animals) resulted in abnormal differentiation of the gubernacula during development and, in about 40% of adult males, unilateral, always left-sided, cryptorchidism. At birth the right testis was positioned above the processus vaginalis and eventually moved into the developing scrotal pouch. In affected mutants the left testis was displaced from the normal position and the left processus vaginalis failed to form. The analysis of testicular descent at different stages of postnatal development suggests that unilateral cryptorchidism might be caused by asymmetry in the positions of the abdominal organs providing a higher degree of mobility for the left testis. Spermatogenesis in GU-WT1KO animals was blocked in cryptorchid testes located in a high pararenal position, but was maintained in testes located in a low abdominal position. Conditional inactivation of both Wt1 and androgen receptor (Ar) genes in the gubernaculum led to a bilateral asymmetrical cryptorchidism in all mutant males, with the left testis again located higher than the right one. The malformations induced by WT1 and AR deficiency in the gubernaculum and processus vaginalis, in combination with mechanical constraints on testis descent, determine the final position of the testes. In summary, our data indicate that WT1 is directly involved in gubernaculum differentiation. Taken together, the results of the study underline the complex nature of testicular descent, with an involvement in this process of several genetic factors and developmental events., (Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)
- Published
- 2013
- Full Text
- View/download PDF
50. Monitoring therapy with MEK inhibitor U0126 in a novel Wilms tumor model in Wt1 knockout Igf2 transgenic mice using 18F-FDG PET with dual-contrast enhanced CT and MRI: early metabolic response without inhibition of tumor growth.
- Author
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Flores LG 2nd, Yeh HH, Soghomonyan S, Young D, Bankson J, Hu Q, Alauddin M, Huff V, and Gelovani JG
- Subjects
- Animals, Female, Immunohistochemistry, Male, Mice, Mice, Knockout, Mitogen-Activated Protein Kinase Kinases antagonists & inhibitors, Wilms Tumor diagnostic imaging, Wilms Tumor pathology, Butadienes pharmacology, Fluorodeoxyglucose F18, Magnetic Resonance Imaging methods, Multimodal Imaging methods, Nitriles pharmacology, Positron-Emission Tomography, Tomography, X-Ray Computed, Wilms Tumor diagnosis, Wilms Tumor drug therapy
- Abstract
Purpose: The understanding of the role of genetic alterations in Wilms tumor development could be greatly advanced using a genetically engineered mouse models that can replicate the development and progression of this disease in human patients and can be monitored using non-invasive structural and molecular imaging optimized for renal tumors., Procedures: Repetitive dual-contrast computed tomography (CT; intravenous and intraperitoneal contrast), T2-weighted magnetic resonance imaging (MRI), and delayed 2-deoxy-2-[(18)F]fluoro-D-glucose ((18)F-FDG) positron emission tomography (PET) were utilized for characterization of Igf2 biallelic expression/Wt1 knockout mouse model of Wilms tumor. For CT imaging, Ioversol 678 mg/ml in 200 μl was administered i.p. followed by 100 μl injected intravenously at 20 and 15 min prior to imaging, respectively. Static PET imaging studies were acquired at 1, 2, and 3 h after i.v. administration of (18)F-FDG (400 μCi). Coronal and sagittal T1-weighted images (TE/TR 8.5/620 ms) were acquired before and immediately after i.v. injection of 0.4 ml/kg gadopentetate dimeglumine followed by T2-weighted images (TE/TR 60/300 ms). Tumor tissue samples were characterized by histopathology and immunohistochemistry for Glut1, FASN, Ki67, and CD34. In addition, six Wt1-Igf2 mice were treated with a mitogen-activated protein kinase (MEK) inhibitor U0126 (50 μmol/kg i.p.) every 4 days for 6 weeks. (18)F-FDG PET/CT imaging was repeated at different days after initiation of therapy with U0126. The percent change of initial tumor volume and SUV was compared to non-treated historic control animals., Results: Overall, the best tumor-to-adjacent kidney contrast as well as soft tissue contrast for other abdominal organs was achieved using T2-weighted MRI. Delayed (18)F-FDG PET (3-h post (18)F-FDG administration) and dual-contrast CT (intravenous and intraperitoneal contrast) provided a more accurate anatomic and metabolic characterization of Wilms tumors in Wt1-Igf2 mice during early development and progression of renal tumors. Over the 8-month period, 46 Wt1-Igf2 mice and 8 littermate control mice were studied. Renal tumors were identified in 54.3 % of Wt1-Igf2 mice between post-natal 50-100 days. In 35.6 % of Wt1-Igf2 mice, tumors were localized in the right kidney; in 24 %, in the left kidney, while 40.4 % of Wt1-Igf2 mice had bilateral kidney tumors. Metastatic lesions were identified in 15.4 % of Wt1-Igf2 mice. Increased levels of Glut1 and IGF1R expression, high Ki67 labeling index, and a dense network of CD34+ microvessels in renal tumors was consistent with increased (18)F-FDG accumulation. Treatment with a MEK 1/2 inhibitor U0126 did not cause the inhibition of tumor growth as compared to untreated animals. However, after the first three to four doses (~2 weeks of treatment), a decrease in (18)F-FDG SUV was observed, as compared to pre-treatment levels (p < 0.05, paired Student t test), which constitutes a metabolic response. Six weeks later, despite continuing therapy, the (18)F-FDG SUV increased again to previous levels., Conclusions: The optimized dual contrast PET/CT imaging with early post i.v. and i.p. contrast CT and 3 h delayed PET imaging after (18)F-FDG administration provides a sensitive and reliable method for detecting early tumor lesions in this endogenous mouse model of Wilms tumor and for monitoring their growth in response to targeted therapies. Therapy with MEK inhibitor U0126 produces only a transient inhibition of tumor glycolytic activity but does not inhibit tumor growth, which is due to continuing IGF2-induced signaling from IGF1R through the PI3K-AKT-mTOR pathway.
- Published
- 2013
- Full Text
- View/download PDF
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