TRIM28-Related Wilms Tumor Predisposition

Mendelian MONDO:0979876 Pathograph 11 Show in embeddings browser hereditary Wilms tumor

TRIM28-related Wilms tumor predisposition (Wilms tumor 7) is an autosomal dominant, incompletely penetrant childhood cancer predisposition caused by heterozygous constitutional loss-of-function variants, mostly truncating or splice-site, in TRIM28, which encodes the KRAB zinc-finger-associated transcriptional corepressor KAP1. Carriers develop Wilms tumors in infancy and early childhood, frequently bilateral, that are characteristically epithelial or epithelial-predominant and arise from perilobar nephrogenic rests. The remaining wild-type allele is lost in the tumor, most often by copy-neutral loss of heterozygosity of chromosome 19q, and the tumors otherwise carry few recurrent Wilms tumor driver mutations. Germline variants account for around 1 per cent of isolated and 8 per cent of familial Wilms tumor. Inherited variants have been maternally transmitted in nearly every reported family. Loss of TRIM28 staining on tumor immunohistochemistry is the practical screen that selects children for germline testing, and carriers are offered renal surveillance and family counselling. No consistent phenotype outside Wilms tumor predisposition has been established.

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1
Inheritance
5
Pathophys.
3
Phenotypes
11
Pathograph
1
Genes
3
Medical Actions
1
Models
1
References
🏷

Classifications

Harrison's Part
ONCOLOGY HEMATOLOGY GENETICS ENVIRONMENT DISEASE
👪

Inheritance

1
Autosomal dominant inheritance HP:0000006
Heterozygous constitutional variants are inherited or arise de novo. Penetrance estimated from the reported pedigrees is about two thirds, an estimate the review authors note is biased upward because families were ascertained through multiple affected members.
Autosomal dominant inheritance Penetrance: INCOMPLETE Penetrance %: 67
Parent-of-origin effect: Strong maternal bias: every inherited variant in the founding exome series, and every patient for whom the parental origin could be established in the 2021 review, had a maternally transmitted variant. A single child with bilateral Wilms tumor after paternal transmission has since been reported, so the bias is not absolute. Genomic imprinting near the PEG3 locus and male subfertility have both been proposed as explanations; neither is established.
Show evidence (5 references)
PMID:33565090 SUPPORT REVIEW SYNTHESIS Human Clinical
"Pedigrees from families with germline pathogenic TRIM28 variants suggest a disease penetrance of ~67%, with 18 affected individuals out of a combined total of 27 (obligate) carriers"
Source for incomplete penetrance and for the 67 per cent figure, derived from the pooled published pedigrees.
PMID:33565090 SUPPORT REVIEW SYNTHESIS Human Clinical
"Since reported families were identified based on the presence of multiple affected individuals, this estimated penetrance is likely biased, but certainly supports offering surveillance to children with germline TRIM28 variants."
Records the ascertainment caveat on the penetrance estimate.
PMID:30885698 SUPPORT Human Clinical
"21 of 33 individuals had a mutation in TRIM28; there was a strong parent-of-origin effect, with all ten inherited mutations being maternally transmitted (p=0·00098)."
The founding exome series establishes the maternal transmission bias.
+ 2 more references
⚙

Pathophysiology

5
Germline TRIM28 Loss-of-Function
A heterozygous constitutional truncating or splice-site TRIM28 allele reduces TRIM28 mRNA and protein and provides the first hit in every cell of the developing kidney.
TRIM28 hgnc:16384 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves decreased TRIM28 (hgnc:16384). hgnc:16384 is a gene from the HUGO Gene Nomenclature Committee. ↓ DECREASED
Genetic context TRIM28 hgnc:16384 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns TRIM28 (hgnc:16384). hgnc:16384 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE allelic_hit_role: FIRST_HIT allelic_event: PATHOGENIC_VARIANT zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Constitutional heterozygous TRIM28 variants; with one exception the reported alleles are truncating or splice-site variants spread across all protein-coding domains.
Downstream
Somatic Loss of the Wild-Type TRIM28 Allele The constitutional allele is present in every nephrogenic cell, so a single somatic event at 19q in a susceptible cell completes biallelic loss.
Show evidence (3 references)
PMID:30694527 SUPPORT Human Clinical
"Expression studies on mRNA and protein level showed reduction of TRIM28, confirming a loss-of-function effect of the mutations identified."
Establishes that the germline alleles are loss of function.
PMID:30694527 SUPPORT Human Clinical
"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."
Names the constitutional heterozygous lesion and its conversion to homozygosity in the tumor.
PMID:33565090 SUPPORT REVIEW SYNTHESIS Human Clinical
"With one exception, the reported variants are truncating or splice site variants located throughout all protein coding domains of the TRIM28 gene"
Summarizes the allele spectrum across all reported patients.
Somatic Loss of the Wild-Type TRIM28 Allele
The remaining wild-type TRIM28 allele is lost in the tumor, most often by somatic recombination on chromosome 19q that makes the mutant allele copy-neutrally homozygous; epigenetic silencing of the second allele is a less frequent route.
metanephric mesenchyme stem cell CL:0000324 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves metanephric mesenchyme stem cell (CL:0000324). CL:0000324 is a cell type from the Cell Ontology.
TRIM28 hgnc:16384 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves decreased TRIM28 (hgnc:16384). hgnc:16384 is a gene from the HUGO Gene Nomenclature Committee. ↓ DECREASED
Genetic context TRIM28 hgnc:16384 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns TRIM28 (hgnc:16384). hgnc:16384 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: SOMATIC allelic_hit_role: SECOND_HIT allelic_event: LOSS_OF_HETEROZYGOSITY allelic_event: PROMOTER_METHYLATION functional_impact_category: LOSS_OF_FUNCTION
Copy-neutral loss of heterozygosity of 19q by mitotic recombination, or less often epigenetic silencing of the retained allele.
kidney UBERON:0002113 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in kidney (UBERON:0002113). UBERON:0002113 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Biallelic TRIM28 Loss in Nephrogenic Precursors
Show evidence (3 references)
PMID:30694527 SUPPORT Human Clinical
"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."
Direct observation of the somatic second hit in tumors from germline carriers.
PMID:33565090 SUPPORT REVIEW SYNTHESIS Human Clinical
"Loss of heterozygosity (LOH) was found to be the most common mechanism for this second hit, which was confirmed in 17 out of 20 cases."
Quantifies loss of heterozygosity as the dominant second-hit route across the published tumors.
PMID:29912901 SUPPORT Human Clinical
"Inactivation of TRIM28, either germline or somatic, occurred through inactivating mutations, loss of heterozygosity or epigenetic silencing."
Adds epigenetic silencing as an alternative inactivating event.
Biallelic TRIM28 Loss in Nephrogenic Precursors
Cells with both TRIM28 alleles inactivated lose nuclear TRIM28 protein and with it KRAB zinc-finger-directed transcriptional corepression. TRIM28-mutant tumors show broad derepression of transposable elements. The biallelic state is already present in the perilobar nephrogenic rests that accompany these tumors, placing it before tumor formation.
metanephric mesenchyme stem cell CL:0000324 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves metanephric mesenchyme stem cell (CL:0000324). CL:0000324 is a cell type from the Cell Ontology.
TRIM28 hgnc:16384 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves absent TRIM28 (hgnc:16384). hgnc:16384 is a gene from the HUGO Gene Nomenclature Committee. ∅ ABSENT
transposable element silencing GO:0010526 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased transposable element silencing (GO:0010526). GO:0010526 is a biological process from the Gene Ontology. ↓ DECREASED
transcription corepressor activity GO:0003714 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased transcription corepressor activity (GO:0003714). GO:0003714 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Arrested Late Nephrogenesis Loss of TRIM28 in the developing kidney is thought to deregulate transcription in nephrogenic progenitors and halt their differentiation; which targets mediate this is not established.
Show evidence (5 references)
PMID:33565090 SUPPORT REVIEW SYNTHESIS Human Clinical
"In children with WT, TRIM28 acts as a classical tumour suppressor gene, with both alleles generally disrupted in the tumour."
States the biallelic state in the tumor.
PMID:29912901 SUPPORT Human Clinical
"Critically, these tumours were negative for TRIM28 immunohistochemical staining whereas the epithelial component in normal tissue and other Wilms tumours stained positively."
Shows loss of TRIM28 protein in the tumor cells against retained staining in normal tissue.
PMID:37792584 SUPPORT Human Clinical
"There was a high prevalence of perilobar nephrogenic rests, putative precursor lesions, that carried the same biallelic TRIM28 alterations in 7/7 cases tested."
Places biallelic TRIM28 loss in the precursor lesions, upstream of the tumor.
+ 2 more references
Arrested Late Nephrogenesis
Nephrogenesis is disturbed late in gestation, so embryonal nephrogenic tissue persists at the periphery of the kidney as perilobar nephrogenic rests rather than completing nephron formation. The perilobar location contrasts with the intralobar rests of germline WT1 disease, which reflect an earlier disturbance.
nephron development GO:0072006 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal nephron development (GO:0072006). GO:0072006 is a biological process from the Gene Ontology. ⚠ ABNORMAL
kidney UBERON:0002113 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in kidney (UBERON:0002113). UBERON:0002113 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Trim28 nephron-progenitor conditional knockout mouse Mouse partially recapitulates Deleting Trim28 in nephron progenitors impairs progenitor maintenance and kidney development.
Downstream
Perilobar Nephrogenic Rests
Epithelial-Type Wilms Tumor Initiation Persisting rests that already carry biallelic TRIM28 loss are the presumed precursors of the tumor; the further events needed for transformation are not established.
Show evidence (2 references)
PMID:33565090 SUPPORT REVIEW SYNTHESIS Human Clinical
"When compared with germline WT1 variants which are associated with intralobar nephrogenic rests, the identification of perilobar nephrogenic rests in patients with germline TRIM28 variants suggests a relatively late disturbance of nephrogenesis, which is normally completed by 34–37 weeks of gestation"
Infers a late nephrogenic arrest from the perilobar rest location in germline carriers.
PMID:42522414 SUPPORT INDIRECT Model Organism
"Thus, our data demonstrate that TRIM28 primarily influences the maintenance and differentiation of NPCs and PT cells, as well as their subsequent function."
Mouse nephron-progenitor deletion shows TRIM28 is required for progenitor maintenance and differentiation. The model deletes both alleles in all progenitors rather than reproducing a germline heterozygote with a somatic second hit.
Epithelial-Type Wilms Tumor Initiation
TRIM28-deficient nephrogenic tissue gives rise to Wilms tumors that are monomorphic epithelial or epithelial-predominant, with a post-induction expression profile, and that carry very few mutations in the recurrent Wilms tumor driver genes, so TRIM28 loss appears to be the main driver. These tumors are usually low stage and have rarely relapsed.
mesenchymal to epithelial transition involved in metanephros morphogenesis GO:0003337 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal mesenchymal to epithelial transition involved in metanephros morphogenesis (GO:0003337). GO:0003337 is a biological process from the Gene Ontology. ⚠ ABNORMAL
kidney UBERON:0002113 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in kidney (UBERON:0002113). UBERON:0002113 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Epithelial-Predominant Wilms Tumor
Bilateral Wilms Tumor Every nephrogenic cell in both kidneys carries the first hit, so independent second hits produce tumors in both kidneys in a third of carriers.
Show evidence (4 references)
PMID:30694527 SUPPORT Human Clinical
"Additionally, the tumors showed very few mutations in known Wilms tumor driver genes, suggesting that loss of TRIM28 is the main driver of tumorigenesis."
Supports TRIM28 loss as the principal driver of tumor initiation.
PMID:37792584 SUPPORT Human Clinical
"TRIM28-mutant tumors otherwise lacked WT-typical IGF2 alterations or driver events, except for rare TP53 progression events that occurred with expected frequency."
Confirms the near absence of other Wilms tumor drivers in a large independent series.
PMID:33565090 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical
"The predominance of epithelial WT suggests that the arrested renal mesenchyme is somehow directed towards epithelial differentiation."
Basis for binding abnormal mesenchymal-to-epithelial transition; the review infers it from the tumor histology rather than measuring it.
+ 1 more reference
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for TRIM28-Related Wilms Tumor Predisposition Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

3
Epithelial-Predominant Wilms Tumor FREQUENT Neoplastic HP:0002667 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epithelial-predominant nephroblastoma, annotated with Nephroblastoma (HP:0002667), qualified as infantile onset. HP:0002667 is a phenotype from the Human Phenotype Ontology.
Onset: INFANTILE
Show evidence (4 references)
PMID:30885698 SUPPORT Human Clinical
"We also found a strong association with the rare epithelial subtype of Wilms tumour, with 14 of 16 tumours being epithelial or epithelial predominant."
Establishes the epithelial histology of tumors in germline carriers.
PMID:33565090 SUPPORT REVIEW SYNTHESIS Human Clinical
"Median age at WT diagnosis was 13 months (range 5–118 months), which is younger compared with general WT cohorts"
Source for the infantile median onset in 30 germline carriers.
PMID:33565090 SUPPORT REVIEW SYNTHESIS Human Clinical
"Follow‐up data were available for 13 patients with germline pathogenic variants in TRIM28, none of whom relapsed."
Supports the favorable outcome stated in the description.
+ 1 more reference
Bilateral Wilms Tumor FREQUENT Neoplastic HP:0002667 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bilateral nephroblastoma, annotated with Nephroblastoma (HP:0002667), qualified as laterality bilateral; infantile onset. HP:0002667 is a phenotype from the Human Phenotype Ontology.
Laterality: BILATERAL Onset: INFANTILE
Show evidence (2 references)
PMID:33565090 SUPPORT REVIEW SYNTHESIS Human Clinical
"Among the 30 patients with germline TRIM28 variants (17 female, 13 male), ten (33%) had bilateral disease."
Gives the bilateral fraction among germline carriers.
PMID:30694527 SUPPORT Human Clinical
"The tumors were bilateral in six patients, and 10/11 tumors are accompanied by perilobar nephrogenic rests."
Independent series reporting bilateral tumors in carriers.
Perilobar Nephrogenic Rests FREQUENT Renal HP:0012782 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Perilobar nephrogenic rest (HP:0012782). HP:0012782 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:33565090 SUPPORT REVIEW SYNTHESIS Human Clinical
"Nephrogenic rests were reported in 11 patients, including 7/10 (70%) with germline TRIM28 variants"
Gives the frequency of nephrogenic rests among germline carriers.
PMID:33565090 SUPPORT REVIEW SYNTHESIS Human Clinical
"All reported nephrogenic rests were perilobar rests."
Supports the perilobar type specifically.
PMID:30694527 SUPPORT Human Clinical
"The tumors were bilateral in six patients, and 10/11 tumors are accompanied by perilobar nephrogenic rests."
Perilobar rests accompanied nearly every tumor in the original germline-carrier series.
🧬

Genetic Associations

1
TRIM28 (Germline tumor suppressor predisposition)
Gene: TRIM28 hgnc:16384 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TRIM28 (hgnc:16384). hgnc:16384 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (3 references)
PMID:29912901 SUPPORT Human Clinical
"Here we report that germline loss of function mutations in TRIM28 predispose children to Wilms tumour."
One of the two independent reports establishing TRIM28 as a Wilms tumor predisposition gene.
PMID:30694527 SUPPORT Human Clinical
"These data establish TRIM28 as a novel Wilms tumor predisposition gene, acting as a tumor suppressor gene by LOH."
Independent establishment of TRIM28 as a predisposition gene acting through loss of heterozygosity.
PMID:30885698 SUPPORT Human Clinical
"There were no TRIM28 mutations in individuals with other childhood or adult cancers."
Supports the tumor-type specificity recorded in notes.
💊

Medical Actions

3
Renal Tumor Surveillance
Action: renal ultrasound surveillanceNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is renal ultrasound surveillance, annotated with Cancer Screening (NCIT:C15406). NCIT:C15406 is a clinical intervention from the NCI Thesaurus. Ontology label: Cancer Screening NCIT:C15406
Platform: Other
Children carrying a germline TRIM28 variant are offered renal ultrasound surveillance. Because a sizeable fraction of carriers present after age five, surveillance continuing to about age eight has been suggested.
Mechanism Target:
Epithelial-Predominant Wilms Tumor — Surveillance detects tumors early rather than preventing tumor initiation, so it is linked to the tumor phenotype, not to the initiation mechanism.
Show evidence (1 reference)
PMID:33565090 SUPPORT REVIEW SYNTHESIS Human Clinical
"We found that 25/30 patients (83%) were diagnosed before the age of 7 years and 28/30 (93%) before the age of 8 years, which may encourage continuing surveillance until the age of 8 years"
Age distribution of tumors in carriers on which the suggested surveillance duration rests.
Genetic Counseling and Cascade Testing
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Platform: Other
Identifying a germline TRIM28 variant allows counselling of the family and testing of at-risk relatives. Counselling should cover Wilms tumor risk for paternally as well as maternally inherited variants.
Show evidence (2 references)
PMID:33565090 SUPPORT REVIEW SYNTHESIS Human Clinical
"Recognizing germline TRIM28 variants in patients with WT can enable counselling, genetic testing, and potential early detection of WT in other children in the family."
States the family benefit of identifying a carrier.
PMID:38282073 SUPPORT Human Clinical
"This finding suggests that genetic counselling for paternally inherited pathogenic variants in TRIM28 should include discussion of a potential risk of Wilms tumour."
Extends counselling to paternally inherited variants.
Standard Wilms Tumor Therapy
Action: chemotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is chemotherapy (NCIT:C15632). NCIT:C15632 is a clinical intervention from the NCI Thesaurus. Ontology label: Chemotherapy NCIT:C15632
Platform: Other
Tumors in carriers are treated with standard Wilms tumor protocols, and the reported responses are good.
Show evidence (1 reference)
PMID:32699065 SUPPORT Human Clinical
"Both were treated with standard therapies with good response and long-term sustained complete remission of 53 and 97 mo, respectively."
Sibling pair with bilateral TRIM28-related tumors in sustained remission after standard therapy.
🔬

Diagnosis

2
TRIM28 immunohistochemistry on Wilms tumor tissue
Loss of nuclear TRIM28 (KAP1) staining in tumor cells with retained staining in surrounding normal cells identifies TRIM28-inactivated tumors and selects patients for germline testing. Review authors recommend applying it to all Wilms tumor histologies, since non-epithelial TRIM28-mutant tumors occur.
TRIM28 immunohistochemistry NCIT:C51944 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:33565090 SUPPORT REVIEW SYNTHESIS Human Clinical
"Therefore, loss of TRIM28 (KAP1/TIF1beta) protein expression in tumour tissue by immunohistochemistry is an effective strategy to identify patients carrying pathogenic TRIM28 variants."
Supports tumor immunohistochemistry as the screen for carriers.
PMID:37792584 SUPPORT Human Clinical
"Given the high prevalence of predisposing variants in TRIM28-driven WT, we suggest that immunohistochemical testing of TRIM28 be integrated into diagnostic practice as the management of WT in predisposed children differs from that with sporadic tumors."
Recommends routine TRIM28 immunohistochemistry on the basis of a large epithelial Wilms tumor series.
Germline TRIM28 genetic testing
Germline sequencing of TRIM28 in blood-derived DNA establishes the diagnosis, and is indicated particularly in children with epithelial Wilms tumor or a TRIM28-negative tumor on immunohistochemistry.
germline TRIM28 genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Results: A heterozygous pathogenic TRIM28 variant in constitutional DNA establishes the diagnosis.
Show evidence (2 references)
PMID:30885698 SUPPORT Human Clinical
"We recommend that all individuals with Wilms tumour should be offered genetic testing and particularly, those with epithelial Wilms tumour should be offered TRIM28 genetic testing."
Recommends germline TRIM28 testing, particularly for epithelial tumors.
PMID:33565090 SUPPORT REVIEW SYNTHESIS Human Clinical
"Subsequently, genetic analysis of TRIM28 in blood‐derived DNA can be performed in all patients who display loss of TRIM28 in the tumour."
Links tumor immunohistochemistry to germline testing.
🐁

Animal Models

1
Trim28 nephron-progenitor conditional knockout mouse
Species
Mouse
Genotype
Trim28 conditional deletion in nephron progenitors (homozygous)
Publication
PMID:42522414
Pathograph links
Arrested Late Nephrogenesis partially recapitulates fidelity: low Deleting Trim28 in nephron progenitors impairs progenitor maintenance and kidney development.
Limitations: Both alleles are deleted in every nephron progenitor, unlike the germline heterozygote with a clonal somatic second hit, and the kidneys formed no tumors or nephrogenic rests.
Show evidence (1 reference)
PMID:42522414 SUPPORT Model Organism
"We found that deleting Trim28 in nephron progenitors resulted in early postnatal lethality and reduced kidney weight."
Shows a kidney developmental defect from nephron-progenitor Trim28 loss.
{ }

Source YAML

click to show 
name: TRIM28-Related Wilms Tumor Predisposition
creation_date: "2026-10-01T04:24:43Z"
description: >-
  TRIM28-related Wilms tumor predisposition (Wilms tumor 7) is an autosomal
  dominant, incompletely penetrant childhood cancer predisposition caused by
  heterozygous constitutional loss-of-function variants, mostly truncating or
  splice-site, in TRIM28, which encodes the KRAB zinc-finger-associated
  transcriptional corepressor KAP1. Carriers develop Wilms tumors in infancy and
  early childhood, frequently bilateral, that are characteristically epithelial
  or epithelial-predominant and arise from perilobar nephrogenic rests. The
  remaining wild-type allele is lost in the tumor, most often by copy-neutral
  loss of heterozygosity of chromosome 19q, and the tumors otherwise carry few
  recurrent Wilms tumor driver mutations. Germline variants account for around 1
  per cent of isolated and 8 per cent of familial Wilms tumor. Inherited variants
  have been maternally transmitted in nearly every reported family. Loss of
  TRIM28 staining on tumor immunohistochemistry is the practical screen that
  selects children for germline testing, and carriers are offered renal
  surveillance and family counselling. No consistent phenotype outside Wilms
  tumor predisposition has been established.
category: Mendelian
parents:
- hereditary Wilms tumor
synonyms:
- Wilms tumor 7
- WT7
- TRIM28-associated Wilms tumor
- TRIM28-related Wilms tumour predisposition
disease_term:
  preferred_term: Wilms tumor 7
  term:
    id: MONDO:0979876
    label: Wilms tumor 7
classifications:
  harrisons_chapter:
  - classification_value: ONCOLOGY_HEMATOLOGY
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
notes: >-
  Curated as a separate entry from Wilms_Tumor under design decision 3a, which
  keeps a germline cancer predisposition condition separate from the tumor it
  predisposes to; MONDO files this class under hereditary Wilms tumor. The tumor
  side of the mechanism is also curated on Wilms_Tumor as the TRIM28 Tumor
  Suppressor Loss node. The file is named for the gene rather than the MONDO
  numbered label because the clinical literature names the condition by gene,
  as other gene-specific predisposition entries here do; the MONDO label is kept
  as a synonym. Additional findings reported in single carriers (autism, speech
  delay, congenital heart defects) and the male subfertility seen in
  heterozygous mice are not curated as phenotypes, because the 2021 review of
  all reported carriers found no strong evidence for any phenotype other than
  Wilms tumor predisposition.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  penetrance_percentage: "67"
  parent_of_origin_effect: >-
    Strong maternal bias: every inherited variant in the founding exome series,
    and every patient for whom the parental origin could be established in the
    2021 review, had a maternally transmitted variant. A single child with
    bilateral Wilms tumor after paternal transmission has since been reported,
    so the bias is not absolute. Genomic imprinting near the PEG3 locus and male
    subfertility have both been proposed as explanations; neither is
    established.
  description: >-
    Heterozygous constitutional variants are inherited or arise de novo.
    Penetrance estimated from the reported pedigrees is about two thirds, an
    estimate the review authors note is biased upward because families were
    ascertained through multiple affected members.
  evidence:
  - reference: PMID:33565090
    reference_title: "TRIM28 variants and Wilms' tumour predisposition."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Pedigrees from families with germline pathogenic TRIM28 variants suggest a disease penetrance of ~67%, with 18 affected individuals out of a combined total of 27 (obligate) carriers"
    explanation: >-
      Source for incomplete penetrance and for the 67 per cent figure, derived
      from the pooled published pedigrees.
  - reference: PMID:33565090
    reference_title: "TRIM28 variants and Wilms' tumour predisposition."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Since reported families were identified based on the presence of multiple affected individuals, this estimated penetrance is likely biased, but certainly supports offering surveillance to children with germline TRIM28 variants."
    explanation: >-
      Records the ascertainment caveat on the penetrance estimate.
  - reference: PMID:30885698
    reference_title: "Identification of new Wilms tumour predisposition genes: an exome sequencing study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "21 of 33 individuals had a mutation in TRIM28; there was a strong parent-of-origin effect, with all ten inherited mutations being maternally transmitted (p=0·00098)."
    explanation: >-
      The founding exome series establishes the maternal transmission bias.
  - reference: PMID:33565090
    reference_title: "TRIM28 variants and Wilms' tumour predisposition."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "A remarkable observation in the families identified thus far was that in all 15 patients with WT for whom parental inheritance could be established, the pathogenic TRIM28 variant was inherited from the mother (three of whom were also diagnosed with WT)"
    explanation: >-
      Extends the maternal transmission observation across all published
      families with established parental origin.
  - reference: PMID:38282073
    reference_title: "Wilms tumour resulting from paternal transmission of a TRIM28 pathogenic variant-A first report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, here we report a child with bilateral Wilms tumour who had inherited a pathogenic TRIM28 variant from their father."
    explanation: >-
      The first paternally transmitted case, which shows the parent-of-origin
      bias is not absolute.
pathophysiology:
- name: Germline TRIM28 Loss-of-Function
  conforms_to: "germline_two_hit_tumor_predisposition#Constitutional First-Hit Tumor Suppressor Inactivation"
  biological_scale: MOLECULAR
  description: >-
    A heterozygous constitutional truncating or splice-site TRIM28 allele reduces
    TRIM28 mRNA and protein and provides the first hit in every cell of the
    developing kidney.
  gene:
    preferred_term: TRIM28
    modifier: DECREASED
    term:
      id: hgnc:16384
      label: TRIM28
  genetic_context:
    gene:
      preferred_term: TRIM28
      term:
        id: hgnc:16384
        label: TRIM28
    variant_origin: GERMLINE
    allelic_hit_role: FIRST_HIT
    allelic_events:
    - PATHOGENIC_VARIANT
    zygosity: HETEROZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Constitutional heterozygous TRIM28 variants; with one exception the
      reported alleles are truncating or splice-site variants spread across all
      protein-coding domains.
  evidence:
  - reference: PMID:30694527
    reference_title: "TRIM28 haploinsufficiency predisposes to Wilms tumor."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Expression studies on mRNA and protein level showed reduction of TRIM28, confirming a loss-of-function effect of the mutations identified."
    explanation: >-
      Establishes that the germline alleles are loss of function.
  - reference: PMID:30694527
    reference_title: "TRIM28 haploinsufficiency predisposes to Wilms tumor."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: >-
      Names the constitutional heterozygous lesion and its conversion to
      homozygosity in the tumor.
  - reference: PMID:33565090
    reference_title: "TRIM28 variants and Wilms' tumour predisposition."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "With one exception, the reported variants are truncating or splice site variants located throughout all protein coding domains of the TRIM28 gene"
    explanation: >-
      Summarizes the allele spectrum across all reported patients.
  downstream:
  - target: Somatic Loss of the Wild-Type TRIM28 Allele
    causal_link_type: DIRECT
    description: >-
      The constitutional allele is present in every nephrogenic cell, so a single
      somatic event at 19q in a susceptible cell completes biallelic loss.
- name: Somatic Loss of the Wild-Type TRIM28 Allele
  conforms_to: "germline_two_hit_tumor_predisposition#Somatic Second-Hit Inactivation of the Wild-Type Allele"
  biological_scale: MOLECULAR
  description: >-
    The remaining wild-type TRIM28 allele is lost in the tumor, most often by
    somatic recombination on chromosome 19q that makes the mutant allele
    copy-neutrally homozygous; epigenetic silencing of the second allele is a
    less frequent route.
  gene:
    preferred_term: TRIM28
    modifier: DECREASED
    term:
      id: hgnc:16384
      label: TRIM28
  genetic_context:
    gene:
      preferred_term: TRIM28
      term:
        id: hgnc:16384
        label: TRIM28
    variant_origin: SOMATIC
    allelic_hit_role: SECOND_HIT
    allelic_events:
    - LOSS_OF_HETEROZYGOSITY
    - PROMOTER_METHYLATION
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Copy-neutral loss of heterozygosity of 19q by mitotic recombination, or
      less often epigenetic silencing of the retained allele.
  cell_types:
  - preferred_term: metanephric mesenchyme stem cell
    term:
      id: CL:0000324
      label: metanephric mesenchyme stem cell
  locations:
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  evidence:
  - reference: PMID:30694527
    reference_title: "TRIM28 haploinsufficiency predisposes to Wilms tumor."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: >-
      Direct observation of the somatic second hit in tumors from germline
      carriers.
  - reference: PMID:33565090
    reference_title: "TRIM28 variants and Wilms' tumour predisposition."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Loss of heterozygosity (LOH) was found to be the most common mechanism for this second hit, which was confirmed in 17 out of 20 cases."
    explanation: >-
      Quantifies loss of heterozygosity as the dominant second-hit route across
      the published tumors.
  - reference: PMID:29912901
    reference_title: "Germline mutations and somatic inactivation of TRIM28 in Wilms tumour."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Inactivation of TRIM28, either germline or somatic, occurred through inactivating mutations, loss of heterozygosity or epigenetic silencing."
    explanation: >-
      Adds epigenetic silencing as an alternative inactivating event.
  downstream:
  - target: Biallelic TRIM28 Loss in Nephrogenic Precursors
    causal_link_type: DIRECT
- name: Biallelic TRIM28 Loss in Nephrogenic Precursors
  conforms_to: "germline_two_hit_tumor_predisposition#Biallelic Tumor Suppressor Inactivation in a Susceptible Cell"
  biological_scale: CELLULAR
  description: >-
    Cells with both TRIM28 alleles inactivated lose nuclear TRIM28 protein and
    with it KRAB zinc-finger-directed transcriptional corepression. TRIM28-mutant
    tumors show broad derepression of transposable elements. The biallelic state
    is already present in the perilobar nephrogenic rests that accompany these
    tumors, placing it before tumor formation.
  gene:
    preferred_term: TRIM28
    modifier: ABSENT
    term:
      id: hgnc:16384
      label: TRIM28
  cell_types:
  - preferred_term: metanephric mesenchyme stem cell
    term:
      id: CL:0000324
      label: metanephric mesenchyme stem cell
  molecular_functions:
  - preferred_term: transcription corepressor activity
    modifier: DECREASED
    term:
      id: GO:0003714
      label: transcription corepressor activity
  biological_processes:
  - preferred_term: transposable element silencing
    modifier: DECREASED
    term:
      id: GO:0010526
      label: transposable element silencing
  evidence:
  - reference: PMID:33565090
    reference_title: "TRIM28 variants and Wilms' tumour predisposition."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "In children with WT, TRIM28 acts as a classical tumour suppressor gene, with both alleles generally disrupted in the tumour."
    explanation: >-
      States the biallelic state in the tumor.
  - reference: PMID:29912901
    reference_title: "Germline mutations and somatic inactivation of TRIM28 in Wilms tumour."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Critically, these tumours were negative for TRIM28 immunohistochemical staining whereas the epithelial component in normal tissue and other Wilms tumours stained positively."
    explanation: >-
      Shows loss of TRIM28 protein in the tumor cells against retained staining
      in normal tissue.
  - reference: PMID:37792584
    reference_title: "TRIM28 inactivation in epithelial nephroblastoma is frequent and often associated with predisposing TRIM28 germline variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There was a high prevalence of perilobar nephrogenic rests, putative precursor lesions, that carried the same biallelic TRIM28 alterations in 7/7 cases tested."
    explanation: >-
      Places biallelic TRIM28 loss in the precursor lesions, upstream of the
      tumor.
  - reference: PMID:33565090
    reference_title: "TRIM28 variants and Wilms' tumour predisposition."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: OTHER
    snippet: "TRIM28 is a ubiquitously expressed corepressor that binds transcription factors in a context-, species-, and cell-type-specific manner to control the expression of genes and transposable elements during embryogenesis and cellular differentiation."
    explanation: >-
      Source for the corepressor and transposable-element silencing functions
      bound on this node. The sentence states what the protein does rather than
      reporting a measurement.
  - reference: PMID:33565090
    reference_title: "TRIM28 variants and Wilms' tumour predisposition."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Finally, a large number of transposable elements across the genome were found to show differential expression, the majority of which were overexpressed"
    explanation: >-
      Transposable-element derepression measured in TRIM28-mutant Wilms tumors,
      supporting the decreased transposable element silencing binding.
  downstream:
  - target: Arrested Late Nephrogenesis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Loss of TRIM28 in the developing kidney is thought to deregulate
      transcription in nephrogenic progenitors and halt their differentiation;
      which targets mediate this is not established.
- name: Arrested Late Nephrogenesis
  biological_scale: TISSUE
  description: >-
    Nephrogenesis is disturbed late in gestation, so embryonal nephrogenic tissue
    persists at the periphery of the kidney as perilobar nephrogenic rests rather
    than completing nephron formation. The perilobar location contrasts with the
    intralobar rests of germline WT1 disease, which reflect an earlier
    disturbance.
  biological_processes:
  - preferred_term: nephron development
    modifier: ABNORMAL
    term:
      id: GO:0072006
      label: nephron development
  locations:
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  evidence:
  - reference: PMID:33565090
    reference_title: "TRIM28 variants and Wilms' tumour predisposition."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "When compared with germline WT1 variants which are associated with intralobar nephrogenic rests, the identification of perilobar nephrogenic rests in patients with germline TRIM28 variants suggests a relatively late disturbance of nephrogenesis, which is normally completed by 34–37 weeks of gestation"
    explanation: >-
      Infers a late nephrogenic arrest from the perilobar rest location in
      germline carriers.
  - reference: PMID:42522414
    reference_title: "The absence of Trim28 in nephron progenitors results in impaired kidney development and function."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Thus, our data demonstrate that TRIM28 primarily influences the maintenance and differentiation of NPCs and PT cells, as well as their subsequent function."
    explanation: >-
      Mouse nephron-progenitor deletion shows TRIM28 is required for progenitor
      maintenance and differentiation. The model deletes both alleles in all
      progenitors rather than reproducing a germline heterozygote with a
      somatic second hit.
  downstream:
  - target: Perilobar Nephrogenic Rests
    causal_link_type: DIRECT
  - target: Epithelial-Type Wilms Tumor Initiation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Persisting rests that already carry biallelic TRIM28 loss are the
      presumed precursors of the tumor; the further events needed for
      transformation are not established.
- name: Epithelial-Type Wilms Tumor Initiation
  conforms_to: "germline_two_hit_tumor_predisposition#Clonal Expansion and Tumor Initiation"
  biological_scale: TISSUE
  description: >-
    TRIM28-deficient nephrogenic tissue gives rise to Wilms tumors that are
    monomorphic epithelial or epithelial-predominant, with a post-induction
    expression profile, and that carry very few mutations in the recurrent Wilms
    tumor driver genes, so TRIM28 loss appears to be the main driver. These
    tumors are usually low stage and have rarely relapsed.
  biological_processes:
  - preferred_term: mesenchymal to epithelial transition involved in metanephros morphogenesis
    modifier: ABNORMAL
    term:
      id: GO:0003337
      label: mesenchymal to epithelial transition involved in metanephros morphogenesis
  locations:
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  evidence:
  - reference: PMID:30694527
    reference_title: "TRIM28 haploinsufficiency predisposes to Wilms tumor."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additionally, the tumors showed very few mutations in known Wilms tumor driver genes, suggesting that loss of TRIM28 is the main driver of tumorigenesis."
    explanation: >-
      Supports TRIM28 loss as the principal driver of tumor initiation.
  - reference: PMID:37792584
    reference_title: "TRIM28 inactivation in epithelial nephroblastoma is frequent and often associated with predisposing TRIM28 germline variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TRIM28-mutant tumors otherwise lacked WT-typical IGF2 alterations or driver events, except for rare TP53 progression events that occurred with expected frequency."
    explanation: >-
      Confirms the near absence of other Wilms tumor drivers in a large
      independent series.
  - reference: PMID:33565090
    reference_title: "TRIM28 variants and Wilms' tumour predisposition."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The predominance of epithelial WT suggests that the arrested renal mesenchyme is somehow directed towards epithelial differentiation."
    explanation: >-
      Basis for binding abnormal mesenchymal-to-epithelial transition; the
      review infers it from the tumor histology rather than measuring it.
  - reference: PMID:37792584
    reference_title: "TRIM28 inactivation in epithelial nephroblastoma is frequent and often associated with predisposing TRIM28 germline variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Expression profiling identified TRIM28-mutant tumors as a homogeneous subset of epithelial WTs that mostly present with stage I disease."
    explanation: >-
      Supports the epithelial, low-stage character of these tumors.
  downstream:
  - target: Epithelial-Predominant Wilms Tumor
    causal_link_type: DIRECT
  - target: Bilateral Wilms Tumor
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Every nephrogenic cell in both kidneys carries the first hit, so
      independent second hits produce tumors in both kidneys in a third of
      carriers.
phenotypes:
- category: Neoplastic
  name: Epithelial-Predominant Wilms Tumor
  description: >-
    Wilms tumor that is monomorphic epithelial or epithelial-predominant in most
    cases, presenting at a median of 13 months, younger than unselected Wilms
    tumor but over a wider age range than germline WT1 disease. Metastatic
    disease has not been reported and no relapse occurred among carriers with
    follow-up data.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Epithelial-predominant nephroblastoma
    term:
      id: HP:0002667
      label: Nephroblastoma
    onset:
      onset_category: INFANTILE
  evidence:
  - reference: PMID:30885698
    reference_title: "Identification of new Wilms tumour predisposition genes: an exome sequencing study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also found a strong association with the rare epithelial subtype of Wilms tumour, with 14 of 16 tumours being epithelial or epithelial predominant."
    explanation: >-
      Establishes the epithelial histology of tumors in germline carriers.
  - reference: PMID:33565090
    reference_title: "TRIM28 variants and Wilms' tumour predisposition."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Median age at WT diagnosis was 13 months (range 5–118 months), which is younger compared with general WT cohorts"
    explanation: >-
      Source for the infantile median onset in 30 germline carriers.
  - reference: PMID:33565090
    reference_title: "TRIM28 variants and Wilms' tumour predisposition."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Follow‐up data were available for 13 patients with germline pathogenic variants in TRIM28, none of whom relapsed."
    explanation: >-
      Supports the favorable outcome stated in the description.
  - reference: PMID:29912901
    reference_title: "Germline mutations and somatic inactivation of TRIM28 in Wilms tumour."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TRIM28-mutated tumours had a monomorphic epithelial histology that is uncommon for Wilms tumour."
    explanation: >-
      Independent series confirming the monomorphic epithelial histology.
- category: Neoplastic
  name: Bilateral Wilms Tumor
  description: >-
    Synchronous or metachronous Wilms tumors in both kidneys, seen in about a
    third of germline carriers.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Bilateral nephroblastoma
    term:
      id: HP:0002667
      label: Nephroblastoma
    laterality: BILATERAL
    onset:
      onset_category: INFANTILE
  evidence:
  - reference: PMID:33565090
    reference_title: "TRIM28 variants and Wilms' tumour predisposition."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Among the 30 patients with germline TRIM28 variants (17 female, 13 male), ten (33%) had bilateral disease."
    explanation: >-
      Gives the bilateral fraction among germline carriers.
  - reference: PMID:30694527
    reference_title: "TRIM28 haploinsufficiency predisposes to Wilms tumor."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The tumors were bilateral in six patients, and 10/11 tumors are accompanied by perilobar nephrogenic rests."
    explanation: >-
      Independent series reporting bilateral tumors in carriers.
- category: Renal
  name: Perilobar Nephrogenic Rests
  description: >-
    Perilobar nephrogenic rests in the kidney surrounding the tumor, found in
    most germline carriers in whom rests were assessed. They carry the same
    biallelic TRIM28 alterations as the tumor and are the presumed precursor
    lesions.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Perilobar nephrogenic rest
    term:
      id: HP:0012782
      label: Perilobar nephrogenic rest
  evidence:
  - reference: PMID:33565090
    reference_title: "TRIM28 variants and Wilms' tumour predisposition."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Nephrogenic rests were reported in 11 patients, including 7/10 (70%) with germline TRIM28 variants"
    explanation: >-
      Gives the frequency of nephrogenic rests among germline carriers.
  - reference: PMID:33565090
    reference_title: "TRIM28 variants and Wilms' tumour predisposition."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "All reported nephrogenic rests were perilobar rests."
    explanation: >-
      Supports the perilobar type specifically.
  - reference: PMID:30694527
    reference_title: "TRIM28 haploinsufficiency predisposes to Wilms tumor."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The tumors were bilateral in six patients, and 10/11 tumors are accompanied by perilobar nephrogenic rests."
    explanation: >-
      Perilobar rests accompanied nearly every tumor in the original
      germline-carrier series.
genetic:
- name: TRIM28
  association: Germline tumor suppressor predisposition
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: TRIM28
    term:
      id: hgnc:16384
      label: TRIM28
  case_fractions:
  - population: isolated Wilms tumor
    case_fraction_percent: 1.0
    notes: Review estimate for germline TRIM28 variants in non-familial Wilms tumor.
    evidence:
    - reference: PMID:33565090
      reference_title: "TRIM28 variants and Wilms' tumour predisposition."
      supports: SUPPORT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: HUMAN_CLINICAL
      snippet: "TRIM28 was recently identified as a Wilms' tumour (WT) predisposition gene, with germline pathogenic variants identified in around 1% of isolated and 8% of familial WT cases."
      explanation: >-
        States the isolated and familial case fractions this record splits into
        two case_fractions entries.
  - population: familial Wilms tumor
    case_fraction_percent: 8.0
    notes: Review estimate for germline TRIM28 variants in familial Wilms tumor.
    evidence:
    - reference: PMID:33565090
      reference_title: "TRIM28 variants and Wilms' tumour predisposition."
      supports: SUPPORT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: HUMAN_CLINICAL
      snippet: "TRIM28 was recently identified as a Wilms' tumour (WT) predisposition gene, with germline pathogenic variants identified in around 1% of isolated and 8% of familial WT cases."
      explanation: >-
        Same review sentence, quoted for the familial fraction.
  notes: >-
    TRIM28 is on distal chromosome 19q. No TRIM28 mutations were found in
    children or adults with other cancers in the founding exome series, so the
    predisposition appears specific to Wilms tumor.
  evidence:
  - reference: PMID:29912901
    reference_title: "Germline mutations and somatic inactivation of TRIM28 in Wilms tumour."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report that germline loss of function mutations in TRIM28 predispose children to Wilms tumour."
    explanation: >-
      One of the two independent reports establishing TRIM28 as a Wilms tumor
      predisposition gene.
  - reference: PMID:30694527
    reference_title: "TRIM28 haploinsufficiency predisposes to Wilms tumor."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These data establish TRIM28 as a novel Wilms tumor predisposition gene, acting as a tumor suppressor gene by LOH."
    explanation: >-
      Independent establishment of TRIM28 as a predisposition gene acting
      through loss of heterozygosity.
  - reference: PMID:30885698
    reference_title: "Identification of new Wilms tumour predisposition genes: an exome sequencing study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There were no TRIM28 mutations in individuals with other childhood or adult cancers."
    explanation: >-
      Supports the tumor-type specificity recorded in notes.
animal_models:
- name: Trim28 nephron-progenitor conditional knockout mouse
  species: Mouse
  genotype: Trim28 conditional deletion in nephron progenitors (homozygous)
  publication: PMID:42522414
  modeled_mechanisms:
  - target: Arrested Late Nephrogenesis
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      Deleting Trim28 in nephron progenitors impairs progenitor maintenance and
      kidney development.
    limitations: >-
      Both alleles are deleted in every nephron progenitor, unlike the germline
      heterozygote with a clonal somatic second hit, and the kidneys formed no
      tumors or nephrogenic rests.
    evidence:
    - reference: PMID:42522414
      reference_title: "The absence of Trim28 in nephron progenitors results in impaired kidney development and function."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We found that deleting Trim28 in nephron progenitors resulted in early postnatal lethality and reduced kidney weight."
      explanation: >-
        Shows a kidney developmental defect from nephron-progenitor Trim28
        loss.
treatments:
- name: Renal Tumor Surveillance
  description: >-
    Children carrying a germline TRIM28 variant are offered renal ultrasound
    surveillance. Because a sizeable fraction of carriers present after age
    five, surveillance continuing to about age eight has been suggested.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: renal ultrasound surveillance
    term:
      id: NCIT:C15406
      label: Cancer Screening
  target_mechanisms:
  - target: Epithelial-Predominant Wilms Tumor
    description: >-
      Surveillance detects tumors early rather than preventing tumor
      initiation, so it is linked to the tumor phenotype, not to the
      initiation mechanism.
  evidence:
  - reference: PMID:33565090
    reference_title: "TRIM28 variants and Wilms' tumour predisposition."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "We found that 25/30 patients (83%) were diagnosed before the age of 7 years and 28/30 (93%) before the age of 8 years, which may encourage continuing surveillance until the age of 8 years"
    explanation: >-
      Age distribution of tumors in carriers on which the suggested surveillance
      duration rests.
- name: Genetic Counseling and Cascade Testing
  description: >-
    Identifying a germline TRIM28 variant allows counselling of the family and
    testing of at-risk relatives. Counselling should cover Wilms tumor risk for
    paternally as well as maternally inherited variants.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:33565090
    reference_title: "TRIM28 variants and Wilms' tumour predisposition."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Recognizing germline TRIM28 variants in patients with WT can enable counselling, genetic testing, and potential early detection of WT in other children in the family."
    explanation: >-
      States the family benefit of identifying a carrier.
  - reference: PMID:38282073
    reference_title: "Wilms tumour resulting from paternal transmission of a TRIM28 pathogenic variant-A first report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This finding suggests that genetic counselling for paternally inherited pathogenic variants in TRIM28 should include discussion of a potential risk of Wilms tumour."
    explanation: >-
      Extends counselling to paternally inherited variants.
- name: Standard Wilms Tumor Therapy
  description: >-
    Tumors in carriers are treated with standard Wilms tumor protocols, and the
    reported responses are good.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: chemotherapy
    term:
      id: NCIT:C15632
      label: Chemotherapy
  evidence:
  - reference: PMID:32699065
    reference_title: "TRIM28 congenital predisposition to Wilms' tumor: novel mutations and presentation in a sibling pair."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both were treated with standard therapies with good response and long-term sustained complete remission of 53 and 97 mo, respectively."
    explanation: >-
      Sibling pair with bilateral TRIM28-related tumors in sustained remission
      after standard therapy.
diagnosis:
- name: TRIM28 immunohistochemistry on Wilms tumor tissue
  diagnosis_term:
    preferred_term: TRIM28 immunohistochemistry
    term:
      id: NCIT:C51944
      label: Immunohistochemical Test
  description: >-
    Loss of nuclear TRIM28 (KAP1) staining in tumor cells with retained staining
    in surrounding normal cells identifies TRIM28-inactivated tumors and selects
    patients for germline testing. Review authors recommend applying it to all
    Wilms tumor histologies, since non-epithelial TRIM28-mutant tumors occur.
  evidence:
  - reference: PMID:33565090
    reference_title: "TRIM28 variants and Wilms' tumour predisposition."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Therefore, loss of TRIM28 (KAP1/TIF1beta) protein expression in tumour tissue by immunohistochemistry is an effective strategy to identify patients carrying pathogenic TRIM28 variants."
    explanation: >-
      Supports tumor immunohistochemistry as the screen for carriers.
  - reference: PMID:37792584
    reference_title: "TRIM28 inactivation in epithelial nephroblastoma is frequent and often associated with predisposing TRIM28 germline variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Given the high prevalence of predisposing variants in TRIM28-driven WT, we suggest that immunohistochemical testing of TRIM28 be integrated into diagnostic practice as the management of WT in predisposed children differs from that with sporadic tumors."
    explanation: >-
      Recommends routine TRIM28 immunohistochemistry on the basis of a large
      epithelial Wilms tumor series.
- name: Germline TRIM28 genetic testing
  diagnosis_term:
    preferred_term: germline TRIM28 genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    Germline sequencing of TRIM28 in blood-derived DNA establishes the diagnosis,
    and is indicated particularly in children with epithelial Wilms tumor or a
    TRIM28-negative tumor on immunohistochemistry.
  results: >-
    A heterozygous pathogenic TRIM28 variant in constitutional DNA establishes
    the diagnosis.
  evidence:
  - reference: PMID:30885698
    reference_title: "Identification of new Wilms tumour predisposition genes: an exome sequencing study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We recommend that all individuals with Wilms tumour should be offered genetic testing and particularly, those with epithelial Wilms tumour should be offered TRIM28 genetic testing."
    explanation: >-
      Recommends germline TRIM28 testing, particularly for epithelial tumors.
  - reference: PMID:33565090
    reference_title: "TRIM28 variants and Wilms' tumour predisposition."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Subsequently, genetic analysis of TRIM28 in blood‐derived DNA can be performed in all patients who display loss of TRIM28 in the tumour."
    explanation: >-
      Links tumor immunohistochemistry to germline testing.
references:
- reference: PMID:20301471
  title: "Wilms Tumor Predisposition."
  tags:
  - GeneReviews
  findings:
  - statement: >-
      The GeneReviews chapter covers Wilms tumor predisposition as a whole; its
      cached record is the summary paragraph only, so no snippet in this entry
      is drawn from it.
datasets: []
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References & Deep Research

References

1
PMID:20301471
Wilms Tumor Predisposition.
1 finding
The GeneReviews chapter covers Wilms tumor predisposition as a whole; its cached record is the summary paragraph only, so no snippet in this entry is drawn from it.