TRIM28 haploinsufficiency predisposes to Wilms tumor

Abstract

Two percent of patients with Wilms tumors have a positive family history. In many of these cases the genetic cause remains unresolved. By applying germline exome sequencing in two families with two affected individuals with Wilms tumors, we identified truncating mutations in TRIM28. Subsequent mutational screening of germline and tumor DNA of 269 children affected by Wilms tumor was performed, and revealed seven additional individuals with germline truncating mutations, and one individual with a somatic truncating mutation in TRIM28. TRIM28 encodes a complex scaffold protein involved in many different processes, including gene silencing, DNA repair and maintenance of genomic integrity. Expression studies on mRNA and protein level showed reduction of TRIM28, confirming a loss‐of‐function effect of the mutations identified. The tumors showed an epithelial‐type histology that stained negative for TRIM28 by immunohistochemistry. The tumors were bilateral in six patients, and 10/11 tumors are accompanied by perilobar nephrogenic rests. Exome sequencing on eight tumor DNA samples from six individuals showed loss‐of‐heterozygosity (LOH) of the TRIM28‐locus by mitotic recombination in seven tumors, suggesting that TRIM28 functions as a tumor suppressor gene in Wilms tumor development. Additionally, the tumors showed very few mutations in known Wilms tumor driver genes, suggesting that loss of TRIM28 is the main driver of tumorigenesis. In conclusion, we identified heterozygous germline truncating mutations in TRIM28 in 11 children with mainly epithelial‐type Wilms tumors, which become homozygous in tumor tissue. These data establish TRIM28 as a novel Wilms tumor predisposition gene, acting as a tumor suppressor gene by LOH.

An eHealth decision‐support tool to prioritize referral practices for genetic evaluation of patients with Wilms tumor

“…In recent decades, genetic testing techniques have evolved substantially with comprehensive next‐generation sequencing initiatives identifying additional genes of interest in larger numbers of oncology patients. Through these studies, pathogenic alterations in novel genes have been identified in patients with WT including CTR9 , TRIM28 , and REST . Although sequencing initiatives are becoming increasingly accessible in large academic institutions (often on a research basis), the majority of practitioners do not have access to these resources and rely on clinical judgment and targeted molecular diagnostic technologies.…”

“…Through these studies, pathogenic alterations in novel genes have been identified in patients with WT including CTR9, TRIM28, and REST. [10][11][12][13] Although sequencing initiatives are becoming increasingly accessible in large academic institutions (often on a research basis), the majority of practitioners do not have access to these resources and rely on clinical judgment and targeted molecular diagnostic technologies. Despite this, CPS identification is becoming more challenging for clinicians with expanding phenotypic diversity as well as a growing spectrum of associated conditions.…”

How I approach hereditary cancer predisposition in a child with cancer

“…The field of hereditary cancer predisposition and genetic testing is rapidly evolving and various new susceptibility genes and interactions will be discovered in the near future . As a consequence, today's genetic test results will be outdated within a few years.…”

“…Thus, even more children may be affected by monogenic CPSs due to additional pathogenic variants in previously unrecognized susceptibility genes. More complex traits, involving cooperative effects of two or more variants in different genes of the same or concurring signaling pathways, and polygenic risk scores have to be considered . Recently, Waszak et al demonstrated that the number of adults affected by genetic cancer predisposition may increase by an additional 10% if mutations in DNA‐repair genes are considered, adding up to an incidence in total of approximately 20% …”

Less may be more for stage I epithelial Wilms tumors

“…Genetic characterization already allows further subclassification of epithelial tumors. TRIM28 inactivation as a driver of epithelial‐type WTs, often already present as a heterozygous germline mutation, clearly defines a specific molecular subgroup among those with an earlier onset . Thus, the 3 cases with bilateral WTs will have a high chance to be explainable by a TRIM28 germline predisposition.…”