Wilms Tumor Predisposition

Purpose.

This GeneReview is intended to help clinicians determine if a genetic basis can be identified in an individual with Wilms tumor in order to provide families with natural history and recurrence risk information.

Goal 1.

Briefly describe the clinical characteristics of Wilms tumor.

Goal 2.

Review the mechanisms of predisposition to Wilms tumor.

Goal 3.

Provide an evaluation strategy to:

• Determine if a proband with Wilms tumor has a predisposition to Wilms tumor;
• Identify the genetic or epigenetic mechanism for Wilms tumor; and
• Determine risks for additional medical complications.

Goal 4.

Discuss genetic counseling issues including mode of inheritance, recurrence risk, and evaluation of relatives at risk based on the underlying genetic mechanism.

Goal 5.

Discuss management (e.g., tumor screening) recommendations for individuals with a genetic predisposition to Wilms tumor.

Surveillance of Children with a Germline Pathogenic Variant or with Wilms Tumor-Associated Syndromes

General considerations. The goal of surveillance in individuals with a genetic predisposition to Wilms tumor is to detect tumors while they are low-stage and require less treatment compared to advanced-stage tumors. Surveillance is not a one-time event and should continue through the period of risk, estimated to be until age five to eight years, depending on the underlying genetic condition. Wilms tumors can double in size every week [Beckwith 1998a], leading to the authors’ recommendation that evaluation with abdominal ultrasound be performed every three months. Because surveillance is associated with economic and psychosocial costs including missed work, anxiety associated with exams, and false-positive results leading to unnecessary interventions, the decision to pursue surveillance requires careful consideration. Weighing the risks and benefits of surveillance, Scott et al [2006] suggested that surveillance be pursued if the risk for tumor development is greater than 5%.

Individuals with a germline WT1 pathogenic variant. Screening by abdominal ultrasound examination is recommended every three months until age five years. Among individuals with Wilms tumor and WAGR syndrome, 90% develop a tumor by age four years and 98% by age seven years [Beckwith 1998b].

Individuals with an 11p15.5 alteration, Beckwith-Wiedemann syndrome (BWS), or isolated hemihyperplasia have a 5% to 7.5% risk of developing Wilms tumor or other malignancies (mainly hepatoblastoma, adrenocortical carcinoma, neuroblastoma, and rhabdomyosarcoma). However, risk of Wilms tumor is restricted to certain subtypes of BWS.

A meta-analysis by Rump et al [2005] of more than 400 individuals with BWS for whom molecular data at 11p15 were available indicated that:

• Wilms tumor was not observed in children with:
  • Loss of methylation at imprinting center 2 (∼45% of BWS);
  • CDKN1C pathogenic variants (∼5-10% of BWS).
• Wilms tumor was observed in children with:
  • Uniparental isodisomy at 11p15 (∼20% of BWS);
  • Gain of methylation at imprinting center 1 (∼10% of BWS);
  • No detectable methylation changes in either imprinting centers 1 or 2 (∼25% of BWS).

Hence, surveillance may be restricted to individuals with uniparental isodisomy at 11p15, gain of methylation at imprinting center 1, or BWS in whom a genetic or epigenetic abnormality is not found. Children with isolated methylation changes of imprinting center 2 or a CDKN1C pathogenic variant do not require surveillance for Wilms tumor. When surveillance is pursued, abdominal ultrasound examination is recommended every three months until age eight years. Among individuals with BWS and Wilms tumor, 81% develop the tumor by age five years and 93% develop the tumor by age eight years [Beckwith 1998a].

Individuals with one of the less common causes of Wilms tumor predisposition. The authors recommend surveillance if the estimated risk for Wilms tumor associated with the genetic variant exceeds 5%. The recommendation can be adjusted depending on the individual preference of the family and treating physician. If the risk period has not been established, surveillance with abdominal ultrasound is recommended every three months until age eight years.

Individuals with bilateral or multifocal Wilms tumor without an identified molecular cause. After completion of therapy for Wilms tumor, individuals should be screened by renal ultrasound examination every three months until age eight years for metachronous tumors. It is assumed that most individuals with bilateral Wilms tumor have a germline variant in a gene predisposing to Wilms tumor, increasing the risk for a metachronous tumor.

Surveillance for Relatives at Risk for Wilms Tumor Predisposition

In families with more than one individual with Wilms tumor and families with one individual with bilateral or multifocal Wilms tumor, it is appropriate to evaluate relatives at risk in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. Evaluations can include the following:

• Molecular genetic testing if the causative genetic alteration has been identified in an affected family. Surveillance with ultrasound may be pursued if the Wilms tumor risk associated with the causative variant is sufficiently high.
• If the causative genetic alteration has not been identified in an affected family member:
  • Offspring of the affected individual should be screened with abdominal ultrasound examination every three months until age eight years.
    Note: The risk for Wilms tumor in the children of survivors of bilateral Wilms tumor is unknown.
  • The benefit of surveillance of sibs of the affected individual is unclear. Only 3% of individuals with bilateral Wilms tumor had an affected family member, indicating that the risk to a sib is even lower than 3%. Surveillance of sibs would not be recommended if applying the threshold risk of tumor greater than 5% as an indication for surveillance.