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.
Highlights
Wilms tumor (WT), the most common renal malignancy in childhood, demonstrates a striking histologic replication of early renal development
All 9 Subset 1 (S1) tumors were included in the TARGET validation set which was analyzed by targeted sequencing for recurrent mutations identified within the TARGET discovery set
TRIM28 itself does not bind to DNA, and requires recruitment by KRAB-zinc finger proteins (ZFPs) to specific genomic sites [22,23]
Summary
Wilms tumor (WT), the most common renal malignancy in childhood, demonstrates a striking histologic replication of early renal development. We and others reported recurrent gene mutations in the majority of WT, with specific mutations occurring with different prevalence in different subsets [5,6,7,8,9,10,11]. These studies (which were confined to high risk WT) did not include the low-risk S1 tumors. In this study we performed comprehensive genomic analysis of S1 tumors, resulting in the identification of recurrent (8/9 patients) mutations in TRIM28, a gene previously recognized to be important both in renal development and in carcinogenesis [12]. Through the investigation of the functional impact of TRIM28 depletion in HEK293 cells we demonstrate over-expression of endogenous retroviruses (ERVs) and associated zinc finger proteins (ZFPs) following TRIM28 depletion, findings we document in TRIM28mutant WTs, thereby validating the functional significance of these mutations
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