Biallelic TRIP13 mutations predispose to Wilms tumor and chromosome missegregation

Yost, Shawn; Wolf, Bas de; Hanks, Sandra; Zachariou, Anna; Marcozzi, Chiara; Clarke, Matthew; Voer, Richarda M. de; Etemad, Banafsheh; Uijttewaal, Esther C. H.; Ramsay, Emma; Wylie, Harriet; Elliott, Anna; Picton, Susan; Smith, Audrey; Smithson, Sarah; Seal, Sheila; Ruark, Elise; Houge, Gunnar; Pines, Jonathon; Kops, Geert J. P. L.; Rahman, Nazneen

doi:10.1038/ng.3883

Cited by 131 publications

(144 citation statements)

References 27 publications

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“…The identification of germline TRIM28 variants in individuals with Wilms tumors is of high clinical significance. Currently, germline genetic testing of individuals with Wilms tumors is performed mainly in individuals with high‐risk histological subtypes, bilateral tumors, syndromic features, or a family history of cancer . Our findings indicate that genetic screening should also be extended to individuals with tumors with epithelial predominant histology, since it is particularly this rare subgroup of patients representing 4.5% of the total group of patients with Wilms tumors, that appears to harbor germline TRIM28 mutations.…”

Section: Discussionmentioning

confidence: 87%

“…Currently, germline genetic testing of individuals with Wilms tumors is performed mainly in individuals with high-risk histological subtypes, bilateral tumors, syndromic features, or a family history of cancer. 6,46 Our findings indicate that genetic screening should also be extended to individuals with tumors with epithelial predominant histology, since it is particularly this rare subgroup of patients representing 4.5% of the total group of patients with Wilms tumors, that appears to harbor germline TRIM28 mutations. Another important finding is the loss of TRIM28 protein expression in tumor cells, which highlights the significance of the inclusion of TRIM28 immunohistochemical staining in the standard pathological analysis of Wilms tumors.…”

Section: Discussionmentioning

confidence: 88%

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TRIM28 haploinsufficiency predisposes to Wilms tumor

Diets

Hoyer

Ekici

et al. 2019

Intl Journal of Cancer

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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.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 88%

TRIM28 haploinsufficiency predisposes to Wilms tumor

Diets

Hoyer

Ekici

et al. 2019

Intl Journal of Cancer

View full text Add to dashboard Cite

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“…Defects in the mitotic checkpoint, also known as the spindle assembly checkpoint (SAC), a cellular surveillance mechanism that ensures mitosis cannot complete until all chromosomes are correctly attached to the mitotic spindle, have also been proposed to contribute to CIN. For example, mutant or deregulated key checkpoint genes have been found in some cancers (Cahill et al 1998, Hernando et al 2004, Ryan et al 2012, and certain cancer predisposition syndromes such as mosaic variegated aneuploidy (MVA) are caused by mutations in checkpoint proteins including BubRI (Hanks et al 2004), CEP57 (Snape et al 2011) and recently TRIP13 (Yost et al 2017). The latter study is particularly interesting as it demonstrated a direct link between TRIP13 downregulation and the development of Wilms tumour in children, and furthermore, suggested that the nature of the MVA-causing mutation dictates the likelihood of cancer developing in the patient (Yost et al 2017).…”

Section: Mechanisms Driving Chromosomal Instabilitymentioning

confidence: 99%

“…For example, mutant or deregulated key checkpoint genes have been found in some cancers (Cahill et al 1998, Hernando et al 2004, Ryan et al 2012, and certain cancer predisposition syndromes such as mosaic variegated aneuploidy (MVA) are caused by mutations in checkpoint proteins including BubRI (Hanks et al 2004), CEP57 (Snape et al 2011) and recently TRIP13 (Yost et al 2017). The latter study is particularly interesting as it demonstrated a direct link between TRIP13 downregulation and the development of Wilms tumour in children, and furthermore, suggested that the nature of the MVA-causing mutation dictates the likelihood of cancer developing in the patient (Yost et al 2017). Functional experiments in cancer cell lines have demonstrated that the mitotic checkpoint retains activity in some cancer cell lines (Gascoigne & Taylor 2008, Burrell et al 2013 but not others (Ryan et al 2012); therefore, mitotic checkpoint dysfunction is unlikely to fully explain cancer CIN.…”

Section: Mechanisms Driving Chromosomal Instabilitymentioning

confidence: 99%

Role of chromosomal instability in cancer progression

McClelland

2017

Endocrine-Related Cancer

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Cancer cells often display chromosomal instability (CIN), a defect that involves loss or rearrangement of the cell's genetic material -chromosomes -during cell division. This process results in the generation of aneuploidy, a deviation from the haploid number of chromosomes, and structural alterations of chromosomes in over 90% of solid tumours and many haematological cancers. This trait is unique to cancer cells as normal cells in the body generally strictly maintain the correct number and structure of chromosomes. This key difference between cancer and normal cells has led to two important hypotheses: (i) cancer cells have had to overcome inherent barriers to changes in chromosomes that are not tolerated in non-cancer cells and (ii) CIN represents a cancer-specific target to allow the specific elimination of cancer cells from the body. To exploit these hypotheses and design novel approaches to treat cancer, a full understanding of the mechanisms driving CIN and how CIN contributes to cancer progression is required. Here, we will discuss the possible mechanisms driving chromosomal instability, how CIN may contribute to the progression at multiple stages of tumour evolution and possible future therapeutic directions based on targeting cancer chromosomal instability.

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“…These indel mutations in protein-coding regions cause frameshifts to generate a null-mutant cell. To date, many disease-model cells generated by this strategy have been reported [53][54][55][56][57]. In the field of human genetics, these null-mutant cells are also used in complementary tests for the candidate variants underlying a genetic disorder called by forward genetics approach.…”

Section: Gene Knockout In Human Cultured Cellsmentioning

confidence: 99%

Updated summary of genome editing technology in human cultured cells linked to human genetics studies

2017

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Current deep-sequencing technology provides a mass of nucleotide variations associated with human genetic disorders to accelerate the identification of causative mutations. To understand the etiology of genetic disorders, reverse genetics in human cultured cells is a useful approach for modeling a disease in vitro. However, gene targeting in human cultured cells is difficult because of their low activity of homologous recombination. Engineered endonucleases enable enhancement of the local activation of DNA repair pathways at the human genome target site to rewrite the desired sequence, thereby efficiently generating disease-modeling cultured cell clones. These edited cells can be used to explore the molecular functions of a causative gene product to uncover the etiological mechanisms. The correction of mutations in patient cells using genome editing technology could contribute to the development of unique gene therapies. This technology can also be applied to screening causative mutations. Rare genetic disorders and non-exonic mutation-caused diseases remain frontier in the field of human genetics as it is difficult to validate whether the extracted nucleotide variants are mutation or polymorphism. When isogenic human cultured cells with a candidate variant reproduce the pathogenic phenotypes, it is confirmed that the variant is a causative mutation.

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Biallelic TRIP13 mutations predispose to Wilms tumor and chromosome missegregation

Abstract: Through exome sequencing we identified six individuals with biallelic loss-of-function mutations in TRIP13. All six developed Wilms tumor. Constitutional mosaic aneuploidies, microcephaly,

Cited by 131 publications

References 27 publications

TRIM28 haploinsufficiency predisposes to Wilms tumor

TRIM28 haploinsufficiency predisposes to Wilms tumor

Role of chromosomal instability in cancer progression

Updated summary of genome editing technology in human cultured cells linked to human genetics studies

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