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Wilms tumour – panel testing

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  • Individuals diagnosed with Wilms tumour.

If a child or young person (CYP) falls outside the target group but the CYP has been diagnosed with 2 or more primary tumours/cancers, or has a significant family history of cancer, or has other features that raise the possibility of a cancer predisposition syndrome, referral to a clinical genetics service for additional phenotyping and consideration of broader genomic testing is recommended (see Paediatric cancer and tumours - referring to genetics).

Note

In the following settings a variant-specific test (rather than sequencing a single gene or gene panel) may be more appropriate and cost effective:

  • Where a known germline pathogenic variant has been identified in a relative.
  • Where a specific pathogenic variant has been identified on somatic tumour testing.

Genetic testing is important for good clinical care of individuals who are suspected of having a familial cancer/tumour predisposition.

Factor Gene Probability of detecting a heritable pathogenic variant
Wilms tumour unselected Epigenetic studies (methylation studies of 11p15 BWSp region) + panel >30%
Panel >10%r

Single gene

WT1

TRIM28

REST

 

7.2%r^#

2%r^#¶

2%r*
Familial Wilms tumour

REST

TRIM28

WT1

H19 hypermethylation

Biallelic BRCA2

Biallelic NYNRIN

CTR9

8%r*

8%r

6%r

Unknown

Unknown

Unknown

Unknown

*Includes children with syndromic diagnosis or minor anomalies
^ Includes children with minor anomalies; children with syndromic diagnosis excluded
# Includes children with a family history of Wilms tumour
¶ Cohort enriched for bilateral disease

When choosing genes to include in a gene panel, care should be taken to select genes which have both clinical validity and clinical utility for the phenotype of concern.

The likelihood of identifying a variant of uncertain significance increases as the number of genes included in a panel increases.

Genes/loci associated with Wilms tumour and associated syndromes
Gene/loci^^ Syndrome(s)/Comment
11p15 epigenetic and genetic changes

Beckwith-Wiedemann syndrome, lateralised overgrowth
ASXL1 (de novo monoallelic) Bohring-Opitz syndrome
BLM (biallelic) Bloom syndrome
BRCA2 (biallelic) Fanconi anaemia
BUB1B (biallelic)/TRIP13 Mosaic variegated aneuploidy
CDC73*

CDC73 (Hyperparathyroidism-jaw tumour syndrome) Wilms tumour can precede other clinical features
CDKN1C (monoallelic) Beckwith-Wiedemann syndrome
CTR9 Rare cause of familial Wilms tumour
DICER1 DICER1 syndrome
DIS3L2 (biallelic) Perlman syndrome
GPC3 and GPC4 (X-linked recessive) Simpson-Golabi-Behmel syndrome
PALB2 (biallelic) Fanconi anaemia
REST Familial Wilms tumour
TP53 Li-Fraumeni syndrome
TRIM28 Epithelial histology is the most common subtype in TRIM28 tumours, however other subtypes have been reported; incomplete penetrance in familial case.
TRIM37 (biallelic) Mulibrey nanism
WT1 (monoallelic) WAGR syndrome, Denys-Drash syndrome, Frasier syndrome, lateralised overgrowth, genitourinary abnormalities. Associated with stromal type Wilms, with nephrogenic rests, bilateral/multifocal tumours, and age <2 years.r

^^ Genes are listed alphabetically; the order of listing does not give any indication of the clinical validity/utility of testing the gene

*Due to the rarity and variable penetrance of CDC73 a clear disease association has not been confirmed 

Predictive testing should never be ordered for a variant of uncertain significance or a benign/likely benign variant.

In addition to sequencing using genomic sequencing (“next generation sequencing” or NGS), a range of other testing methodologies may be needed to identify pathogenic changes in the genes in the panel including:

Information about DNA tests and testing laboratories is available from:

A variant-specific test (rather than sequencing a single gene or gene panel) may be more appropriate and cost effective where a relative is known to have a germline pathogenic variant or a pathogenic variant has been identified in the patient’s tumour.

If these genes are tested using genomic sequencing (“next generation sequencing” or NGS), and testing has not identified a pathogenic variant, the value of testing using another methodology should be considered.

If genetic testing in DNA from peripheral blood does not identify a pathogenic variant, testing of other tumour and tissue samples may be indicated to assess for mosaicism.

Result Reference databases Considerations and advice
Pathogenic variant search
Pathogenic variant ClinVar Wilms tumour – risk management
Variant of uncertain significance

Review pathogenicity of variants periodically

Identify other genes for which a pathogenic variant search could be considered
No reportable variant  

Identify other genes for which a pathogenic variant search could be considered 

If a pathogenic variant is identified, refer to a clinical genetics service or familial cancer centre for review, family risk notification and predictive testing.

If a variant of uncertain significance is identified, consider referral to a clinical genetics service or familial cancer centre for review and guidance.

If a mosaic pathogenic variant is identified, refer to a clinical genetics service or familial cancer centre for review and guidance about the penetrance of phenotypic features (including cancer risk).

For additional information about the management of genetic test results when ordered by a non-genetic healthcare professional refer to eviQ’s Guide for health professionals ordering genetic testing.

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Bibliography

Dumoucel, S., M. Gauthier-Villars, D. Stoppa-Lyonnet, et al. 2014. "Malformations, genetic abnormalities, and Wilms tumor." Pediatr Blood Cancer 61(1): 140-144.

BACKGROUND: Wilms Tumor (WT) can occur in association with tumor predisposition syndromes and/or with clinical malformations. These associations have not been fully characterized at a clinical and molecular genetic level. This study aims to describe clinical malformations, genetic abnormalities, and tumor predisposition syndromes in patients with WT and to propose guidelines regarding indications for clinical and molecular genetic explorations. PROCEDURE: This retrospective study analyzed clinical abnormalities and predisposition syndromes among 295 patients treated for WT between 1986 and 2009 in a single pediatric oncological center. RESULTS: Clinically identified malformations and predisposition syndromes were observed in 52/295 patients (17.6%). Genetically proven tumor predisposition syndromes (n = 14) frequently observed were syndromes associated with alterations of the chromosome WT1 region such as WAGR (n = 6) and Denys-Drash syndromes (n = 3), syndromes associated with alterations of the WT2 region (Beckwith-Wiedeman syndrome, n = 3), and Fanconi anemia (n = 2). Hemihypertrophy and genito-urinary malformations (n = 12 and n = 16, respectively) were the most frequently identified malformations. Other different syndromes or malformations (n = 10) were less frequent. Median age of WT diagnosis was significantly earlier for children with malformations than those without (27 months vs. 37 months, P = 0.0009). There was no significant difference in terms of 5-year EFS and OS between WT patients without or with malformations. CONCLUSIONS: The frequency of malformations observed in patients with WT underline the need of genetic counseling and molecular genetic explorations for a better follow-up of these patients, with a frequently good outcome. A decisional tree, based on clinical observations of patients with WT, is proposed to guide clinicians for further molecular genetic explorations.

Gadd, S., V. Huff, A. L. Walz, et al. 2017. "A Children's Oncology Group and TARGET initiative exploring the genetic landscape of Wilms tumor." Nat Genet 49(10): 1487-1494.

We performed genome-wide sequencing and analyzed mRNA and miRNA expression, DNA copy number, and DNA methylation in 117 Wilms tumors, followed by targeted sequencing of 651 Wilms tumors. In addition to genes previously implicated in Wilms tumors (WT1, CTNNB1, AMER1, DROSHA, DGCR8, XPO5, DICER1, SIX1, SIX2, MLLT1, MYCN, and TP53), we identified mutations in genes not previously recognized as recurrently involved in Wilms tumors, the most frequent being BCOR, BCORL1, NONO, MAX, COL6A3, ASXL1, MAP3K4, and ARID1A. DNA copy number changes resulted in recurrent 1q gain, MYCN amplification, LIN28B gain, and MIRLET7A loss. Unexpected germline variants involved PALB2 and CHEK2. Integrated analyses support two major classes of genetic changes that preserve the progenitor state and/or interrupt normal development.

Version 4

Date Summary of changes
8/03/2023

The following section of the document was updated:

  • Genes that might be included in a Wilms tumour panel
    • Added footnote "Due to the rarity and variable penetrance of CDC73 and PIK3CA a clear disease association has not been confirmed"

Version number increased to V.4.
13/12/2023 'Genes that might be included in a Wilms tumour panel' table discussed at paediatric reference committee meeting July 2023. Decision to remove PIK3CA from table.

Version 3

Date Summary of changes
23/01/2023

The following sections of the document were updated to align with the new eviQ cancer genetics panel testing template:

  • Target population: 
    • added note "In the following settings a variant-specific test (rather than sequencing a single gene or gene panel) may be more appropriate and cost effective:
      • Where a known germline pathogenic variant has been identified in a relative
      • Where a specific pathogenic variant has been identified on somatic tumour testing"
  • Genes that might be included in a panel
    • Wording updated and links to relevant eviQ risk management guidelines added
  • Circumstances in which testing is not indicated:
    • Removed "A variant-specific test (rather than sequencing a single gene or gene panel) may be more cost effective and appropriate where: 
      • a specific pathogenic variant has been identified on somatic tumour testing.
      • a known pathogenic variant has been identified in a relative."
    • Added "Predictive testing should never be ordered for a variant of uncertain significance or a benign/likely benign variant"
  • Testing methods:
    • Added "A variant-specific test (rather than sequencing a single gene or gene panel) may be more appropriate and cost effective where a relative is known to have a germline pathogenic variant or a pathogenic variant has been identified in the patient’s tumour."
    • Removed "MLPA and Sanger sequencing"
  • Result interpretation:
    • Template sentence added.

Version number increased to V.3.

Version 2

Date Summary of changes
15/12/2022

Protocol reviewed at the cancer genetics paediatric reference committee meeting June 2022. Summary of changes:

  • Target population: features of Wilms tumour removed
  • Investigations before panel testing: additional resources added. Link to ID 4246 Wilms tumour investigations to consider added
  • Probability of a heritable pathogenic variant: table reformatted and additional figures added
  • Genes that might be included in a Wilms tumour panel: table reformatted.

Version increase V.2. Review in 2 years.

Version 1

Date Summary of changes
27/05/2021 New protocol developed and discussed by the cancer genetics paediatric reference committee at the February 2020 reference committee meeting. Discussions continued via email and MS Teams. Protocol approved for publication as V.1. Review in 1 year.
13/10/2021 Protocol title changed from 'Wilms tumour panel testing' to 'Wilms tumour – panel testing'.
18/10/2021 'Genes that might be included in a Wilms tumour panel' section updated to indicate inheritance for each of the genes listed in the first table.
10/11/2021 Removed link to "European Directory of DNA Diagnostic Laboratories"

The information contained in this document is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to care or treatment. Any clinician seeking to apply or consult this document is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. While eviQ endeavours to link to reliable sources that provide accurate information, eviQ and the Cancer Institute NSW do not endorse or accept responsibility for the accuracy, currency, reliability or correctness of the content of linked external information sources. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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https://www.eviq.org.au/p/3703

10 Sep 2024