Perilobar Nephrogenic Rests Are Nonobligate Molecular Genetic Precursor Lesions of Insulin-Like Growth Factor-II-Associated Wilms Tumors

Vuononvirta, Raisa; Sebire, Neil J.; Dallosso, Anthony R.; Reis‐Filho, Jorge S.; Williams, Richard D.; Mackay, Alan; Fenwick, Kerry; Grigoriadis, Anita; Ashworth, Alan; Pritchard‐Jones, Kathy; Brown, Keith; Vujanić, Gordan; Jones, Chris

doi:10.1158/1078-0432.ccr-08-1620

Cited by 33 publications

(38 citation statements)

References 32 publications

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“…Thus, at least in the sections analyzed from these five cases, cells with 16q deletions were confined to blastemal or blastemal-anaplastic elements and in no case were they present in all of the neoplastic cells ( Figure 1H). These results are largely consistent with recently published aCGH data on microdissected material, 34 showing that 16q deletions are typically not present in perilobar nephrogenic rests adjacent to tumors with 16q deletions, suggesting that 16q deletions are late events in Wilms tumor development. Based on these collective data, we hypothesized that 16q deletions promote a block of differentiation in blastemal cells, preventing differentiation toward more mature tissue elements in favor of self-renewal of blastemal cells and histological progression toward anaplasia.…”

Section: Q Deletions Are Confined To Immature Tumor Tissue Elementssupporting

confidence: 92%

“…34 Based on this, the authors suggested that 16q deletions are late events in Wilms tumorigenesis, preceded by genetic and epigenetic up-regulation of IGF2. Consistent with this, we found that 16q deletions are typically confined to blastemal components with or without anaplastic features in Wilms tumor and are rare/absent in nephrogenic rests and maturing tumor elements (stromal and epithelial).…”

Section: Discussionmentioning

confidence: 99%

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Deletions of 16q in Wilms Tumors Localize to Blastemal-Anaplastic Cells and Are Associated with Reduced Expression of the IRXB Renal Tubulogenesis Gene Cluster

Mengelbier

Karlsson

Lindgren

et al. 2010

The American Journal of Pathology

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Wilms tumor is the most common pediatric renal neoplasm, but few molecular prognostic markers have been identified for this tumor. Somatic deletion in the long arm of chromosome 16 (16q) is known to predict a less favorable outcome in Wilms tumor, but the underlying molecular mechanisms are not known. We show that 16q deletions are typically confined to immature anaplastic-blastic tumor elements, while deletions are absent in maturing tumor components. The smallest region of deletion overlap mapped to a 1.8-Mb segment containing the IRXB gene cluster including IRX3, IRX5, and IRX6, of which IRX3 is a recently identified regulator of tubular maturation during nephrogenesis. Tumors with 16q deletion showed a lower overall mRNA expression of IRXB genes, and 16q-deleted tumor cells failed to express IRX3 while it was expressed in differentiating tubular tumor elements with intact 16q. Consistent with a role for IRX3 in tubular differentiation, gene sets linked to Notch signaling, Rho signaling, and ion channel activity were enriched in tumors with high IRX3 expression, while WTs with low expression were enriched for gene sets linked to cell cycle progression. Wilms tumor accounts for more than 95% of kidney tumors in children. The majority of patients receiving modern multimodal therapy are cured, but 10 to 15% still die of disease.1 Histologically, most WTs mimic the fetal developing kidney in which immature cells of the metanephric mesenchyme differentiate into stromal and epithelial elements, the latter of which ultimately give rise to the nephronic tubules and glomeruli.2 The notion that Wilms tumor originates from pluripotent immature cells is supported by its characteristic triphasic histology, including blastemal, epithelial, and stromal components. The blastema consists of undifferentiated mesenchymal cells, resembling the metanephric mesenchyme, while the epithelial component might show different degrees of differentiation, including primitive tubular and glomeruloid formations. Gene expression studies have provided additional evidence for the hypothesis that Wilms tumor results from a differentiation block in embryonic kidney formation; genes overexpressed in Wilms tumor are also

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Section: Q Deletions Are Confined To Immature Tumor Tissue Elementssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Deletions of 16q in Wilms Tumors Localize to Blastemal-Anaplastic Cells and Are Associated with Reduced Expression of the IRXB Renal Tubulogenesis Gene Cluster

Mengelbier

Karlsson

Lindgren

et al. 2010

The American Journal of Pathology

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“…21,22 Other common genetic imbalances such as þ 12 and þ 1q/À16q were also not found in our cases of metanephric adenoma. [23][24][25][26] We did not observe amplification of 7q corresponding to isochromosome 7q observed in adult Wilms' tumors. 27 Despite some phenotypic overlap between metanephric adenoma and predominantly epithelial Wilms' tumor (immunoreactivity for WT-1, for example), there was no evidence to indicate any association between the two neoplasms from the molecular genetic point of view.…”

Section: Discussioncontrasting

confidence: 57%

Detection of chromosome copy number alterations in metanephric adenomas by array comparative genomic hybridization

Pan

Epstein

2010

Modern Pathology

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Metanephric adenoma is a rare benign renal tumor typically found in adults. Previous cytogenetic analyses, including karyotyping, fluorescence in situ hybridization (FISH), and comparative genomic hybridization, have yielded conflicting results regarding the somatic genetic aberrations of these tumors. In this study, we investigated the genomic profile of nine cases of metanephric adenoma using array comparative genomic hybridization. Two cases revealed multiple chromosomal gains and losses. Three cases showed sporadic chromosomal imbalances involving no more than three chromosomes. Four cases showed normal chromosome copy numbers. The gain of chromosome 19 was the most common finding (five cases), and FISH using 19p and 19q telomeric probes further confirmed this finding. We did not observe consistent gains of chromosomes 7 and 17, which are common in papillary renal cell carcinoma, neither did we find chromosomal alterations frequently present in Wilms' tumors, including chromosome gains of 1q, 7q, and 12, and losses of 11p and 16q. Our series demonstrates that the genetic profile of metanephric adenoma is fundamentally distinct from those of papillary renal cell carcinoma and Wilms' tumor. Modern Pathology (2010) 23, 1634-1640; doi:10.1038/modpathol.2010.162; published online 27 August 2010Keywords: array comparative genomic hybridization; fluorescence in situ hybridization; metanephric adenoma On the basis of the WHO classification of renal tumors, metanephric tumors comprise metanephric adenomas, metanephric adenofibromas, and metanephric stromal tumors, 1 with each of these having its own characteristic clinicopathological presentation. Metanephric adenoma is defined as a highly cellular epithelial tumor composed of small, uniform, and embryonic-appearing cells. The tumor occurs most commonly in patients in their 50s and 60s, with a female preponderance. Although the vast majority of metanephric adenomas behave in a benign fashion, cases of regional lymph node metastasis and sarcomatoid changes have been individually reported. [2][3][4] The morphological and immunohistochemical characteristics of metanephric adenomas have been well described. 5-7 However, cytogenetic or molecular genetic data about this rare tumor are limited and have mostly been reported for single cases. Previous karyotyping of a total of five cases revealed negative findings, with the exception of a dual balanced translocation of t(1;22)(q22;13) and t(15;16)(q21;p13) in one case. 5,[8][9][10][11][12] One fluorescence in situ hybridization (FISH) study indicated gain of chromosomes 7 and 17 and loss of Y chromosome-the cytogenetic markers of papillary renal cell carcinoma-in 8 of 11 metanephric adenomas. 13 However, subsequent FISH analyses revealed normal copy numbers for chromosomes 7 and 17. 4,8,11,14,15 A deletion in chromosome 2p was the only genetic abnormality described in one tumor, and a tumor suppressor gene region on 2p13 was delineated. 16,17 Most recently, a study employing array comparative genomic hybridization (aCGH) repo...

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“…Nephrogenic rests do not always develop into Wilms tumours however, and the majority of them undergo regression or involution 16 17. Genetic studies of nephrogenic rest and paired tumour tissue have previously yielded insight into the genetic events associated with progression to Wilms tumour.…”

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confidence: 99%

WTX mutations can occur both early and late in the pathogenesis of Wilms tumour

Fukuzawa

Holman

Chow

et al. 2010

Journal of Medical Genetics

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Perilobar Nephrogenic Rests Are Nonobligate Molecular Genetic Precursor Lesions of Insulin-Like Growth Factor-II-Associated Wilms Tumors

Cited by 33 publications

References 32 publications

Deletions of 16q in Wilms Tumors Localize to Blastemal-Anaplastic Cells and Are Associated with Reduced Expression of the IRXB Renal Tubulogenesis Gene Cluster

Deletions of 16q in Wilms Tumors Localize to Blastemal-Anaplastic Cells and Are Associated with Reduced Expression of the IRXB Renal Tubulogenesis Gene Cluster

Detection of chromosome copy number alterations in metanephric adenomas by array comparative genomic hybridization

WTX mutations can occur both early and late in the pathogenesis of Wilms tumour

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