Germline mutations and somatic inactivation of TRIM28 in Wilms tumour

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.

TRIM28 haploinsufficiency predisposes to Wilms tumor

“…Recently, an association of germline and somatic mutations in TRIM28 with Wilms tumor development was reported by Halliday and coworkers . Their findings, namely a predominantly epithelial histology of the tumors, LOH of the TRIM28 mutation in the tumor and a lack of somatic mutations in known Wilms tumor drivers in two tumors examined, are largely in agreement with ours.…”

“…( a ) Schematic representation of the TRIM28 protein and the localization of all identified germline TRIM28 mutations. In black, variants found in this study, and in gray, variants identified by Halliday et al . The TRIM28 protein consists of a RBCC domain (amino acids 65–376), consisting of a RING‐type zinc finger (amino acids 65–121), two B‐boxes (amino acids 148–195, 204–245) and a CC‐domain amino acids (246–376), which is involved in the interaction with the KRAB domain of KRAB zinc finger proteins.…”

“…Taken together, we consider that immunohistochemistry in combination with histology analysis would strongly contribute to the recognition of most of these patients. In recent years, multiple novel Wilms tumor predisposition genes have been identified in nonsyndromic children and children with sporadic Wilms tumors, including the gene identified in this study. Therefore, it could be beneficial to perform sequencing of a Wilms tumor predisposition gene panel including these genes on all children diagnosed with Wilms tumor, irrespective of their histological subtype or family history.…”

“…1Driver genes in Wilms tumor are defined as the genes identified as recurrently mutated according to Refs. …”

“…Interestingly, in all individuals and families with germline TRIM28 mutations identified so far and in which testing of parental DNA was possible, the mutations are maternally inherited (N = 4) . It has been shown that loss of maternal TRIM28 in mice leads to early lethality, which is likely the result of misregulation of genomic imprinting.…”