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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.

Holmquist Mengelbier, Linda LU ; Karlsson, Jenny LU ; Lindgren, David LU ; Øra, Ingrid LU ; Isaksson, Margareth LU ; Frigyesi, Ildiko LU ; Frigyesi, Attila LU ; Bras, Johannes; Sandstedt, Bengt and Gisselsson Nord, David LU (2010) In American Journal of Pathology 177(5). p.2609-2621
Abstract
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... (More)
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. Low mRNA levels of IRXB genes were associated with diffuse anaplasia, high-stage disease, and death. A disturbed balance between tubular differentiation and self-renewal of anaplastic-blastic elements may thus be one mechanism linking 16q deletion to adverse outcome in Wilms tumor. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
American Journal of Pathology
volume
177
issue
5
pages
2609 - 2621
publisher
American Society for Investigative Pathology
external identifiers
  • wos:000284182900045
  • pmid:20847289
  • scopus:78149331302
ISSN
1525-2191
DOI
10.2353/ajpath.2010.100130
language
English
LU publication?
yes
id
be5dac4b-56b2-4d4c-809a-9f3e9ab20a6f (old id 1688132)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/20847289?dopt=Abstract
date added to LUP
2010-10-06 07:32:34
date last changed
2018-07-15 03:15:01
@article{be5dac4b-56b2-4d4c-809a-9f3e9ab20a6f,
  abstract     = {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. Low mRNA levels of IRXB genes were associated with diffuse anaplasia, high-stage disease, and death. A disturbed balance between tubular differentiation and self-renewal of anaplastic-blastic elements may thus be one mechanism linking 16q deletion to adverse outcome in Wilms tumor.},
  author       = {Holmquist Mengelbier, Linda and Karlsson, Jenny and Lindgren, David and Øra, Ingrid and Isaksson, Margareth and Frigyesi, Ildiko and Frigyesi, Attila and Bras, Johannes and Sandstedt, Bengt and Gisselsson Nord, David},
  issn         = {1525-2191},
  language     = {eng},
  number       = {5},
  pages        = {2609--2621},
  publisher    = {American Society for Investigative Pathology},
  series       = {American Journal of Pathology},
  title        = {Deletions of 16q in Wilms Tumors Localize to Blastemal-Anaplastic Cells and Are Associated with Reduced Expression of the IRXB Renal Tubulogenesis Gene Cluster.},
  url          = {http://dx.doi.org/10.2353/ajpath.2010.100130},
  volume       = {177},
  year         = {2010},
}