Abstract
Wilms tumour is a childhood tumour that arises as a consequence of somatic and rare germline mutations, the characterisation of which has refined our understanding of nephrogenesis and carcinogenesis. Here we report that germline loss of function mutations in TRIM28 predispose children to Wilms tumour. Loss of function of this transcriptional co-repressor, which has a role in nephrogenesis, has not previously been associated with cancer. Inactivation of TRIM28, either germline or somatic, occurred through inactivating mutations, loss of heterozygosity or epigenetic silencing. TRIM28-mutated tumours had a monomorphic epithelial histology that is uncommon for Wilms tumour. Critically, these tumours were negative for TRIM28 immunohistochemical staining whereas the epithelial component in normal tissue and other Wilms tumours stained positively. These data, together with a characteristic gene expression profile, suggest that inactivation of TRIM28 provides the molecular basis for defining a previously described subtype of Wilms tumour, that has early age of onset and excellent prognosis.
Highlights
The study of Wilms tumour, a rare childhood kidney tumour [1], has facilitated the discovery of mechanisms of organogenesis and the neoplastic transformation of embryonic tissue
The germline and somatic molecular events associated with Wilms tumour, a childhood kidney cancer, have been progressively defined over the past three decades
Among the uncharacterised tumours are a group of tumours that have monomorphic epithelial histology, familial association, distinctively clustered gene-expression patterns, early age of diagnosis, and excellent prognosis
Summary
The study of Wilms tumour, a rare childhood kidney tumour [1], has facilitated the discovery of mechanisms of organogenesis and the neoplastic transformation of embryonic tissue. The discovery of inactivating mutations and deletions of WT1 in Wilms tumours [2] led to the revelation of its key roles in development of numerous embryonic tissues [3, 4]. Mutations in microRNA processors DGCR8, DROSHA, and DICER1 have underscored the importance of this pathway in developmental tumours [8,9,10,11], whereas mutations in SIX1 and SIX2 reflect their critical role in renal development [9, 10, 12]. Characterisation of other recently reported recurrent somatic mutations [9, 10, 13] will further clarify the mechanisms of nephrogenesis and neoplasia
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