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

Amy E. Armstrong, Samantha L Gadd, Vicki Huff, Daniela S. Gerhard, Jeffrey S. Dome, Elizabeth J Perlman*

*Corresponding author for this work

Research output: Contribution to journalArticle

3 Citations (Scopus)

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 oncogen-esis remains elusive.

Original languageEnglish (US)
Article numbere0208936
JournalPloS one
Volume13
Issue number12
DOIs
StatePublished - Dec 1 2018

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Oncology
Wilms Tumor
Set theory
Tumors
Genes
kidneys
Kidney
neoplasms
Endogenous Retroviruses
Retroviridae
genes
Anaplasia
Developmental Genes
Neoplasms
Mutation
Germ-Line Mutation
HEK293 Cells
Loss of Heterozygosity
DNA Methylation
Carcinogens

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

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title = "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",
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 oncogen-esis remains elusive.",
author = "Armstrong, {Amy E.} and Gadd, {Samantha L} and Vicki Huff and Gerhard, {Daniela S.} and Dome, {Jeffrey S.} and Perlman, {Elizabeth J}",
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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. / Armstrong, Amy E.; Gadd, Samantha L; Huff, Vicki; Gerhard, Daniela S.; Dome, Jeffrey S.; Perlman, Elizabeth J.

In: PloS one, Vol. 13, No. 12, e0208936, 01.12.2018.

Research output: Contribution to journalArticle

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AU - Perlman, Elizabeth J

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