The impact of genetic predisposition in pediatric renal cancer: genotypic and phenotypic characterization

Cancer in children is sometimes caused by genetic predisposition. For pediatric
renal tumors, a genetic predisposition is currently recognized or suspected in
10-20% of children. However, the true incidence of renal tumor predisposition
in children is still unknown. Recognizing genetic predisposition is important
to provide a targeted therapeutic approach, early genetic counseling and
screening of family members at risk.

Wilms tumor is the most common renal tumor in childhood. This tumor is rare in
adults, and can occur in children sporadically, or as a result of a renal tumor
predisposition syndrome. Well known predisposition syndromes include
Denys-Drash, WAGR and Beckwith-Wiedemann syndrome. Children with these
syndromes can often be recognized by their appearance, a family history of
cancer or congenital abnormalities. However, genetic predisposition has also
been described in children without any of these features. It is therefore
unclear who should be referred for genetic testing.

Also in non-Wilms tumors, germline genetic abberations have been identified
that can explain the development of the renal tumor in a some of the children.
Examples include the recently described DICER1 syndrome in children with a
cystic nephroma, and SMARCB1 mutations in children with a rhabdoid tumor of the
kidney. Yet, information on phenotypic characteristics and the role of genetic
predisposition in other renal tumors in childhood is scarce.

1. To determine the frequency of mutations in known and novel pediatric renal
cancer predisposing genes.

2. To structurally document phenotypic characteristics of children with renal
cancer, to optimize genetic counseling and surveillance and contribute to a
better detection of pediatric renal cancer predisposition.

All children with renal tumors in the Netherlands, and some adults with Wilms
tumors, are treated in the Princess Máxima Center. They are referred to the
clinical geneticist for genetic counseling, and will be registered in the
WES-KidTs study.

WES-KidTs consists of standardized phenotyping, genetic characterization and
the development of a guideline for genetic counseling and testing. Standardized
phenotyping includes documentation of syndromic features, tumor type,
psychomotor development and medical and family history. Based on this
information, patients will be stratified into three categories:
a. Patients highly suspected for a specific renal cancer predisposition
syndrome, which justifies direct testing with a gene-specific test
b. Patients with features/history suspect for genetic susceptibility without a
clear candidate gene
c. Patients without suspicion for genetic predisposition

Patients in the first category, with a high suspicion of a predisposition
syndrome, will be offered gene-specific testing as part of routine diagnostics.
Patients with Wilms tumor will also be offered methylation analysis to test for
Beckwith Wiedemann Syndrome.

Patients in whom gene-specific testing did not lead to a genetic diagnosis, and
patients from the last two categories, will be asked to participate in whole
exome sequencing (WES). WES will be performed in two steps:

Step 1: In this step, exome data will be analysed using a renal cancer
predisposition gene filter, to minimize unsollicted findings. Only genes for
which mutations are currently known to carry an increased risk of renal cancer
are included in this filter.
Step 2: If the filtered WES-analysis has not identified a genetic
predisposition, we can perform a trio-analysis in which we compare the
patient's complete WES data to WES data from both parents. Patients and/or
parents can indicate on the informed consent form whether our analysis should
be limited to the renal cancer gene filter (step 2) or whether a trio-analysis
can be performed (step 3).

The results of this study will be used to develop a guideline for genetic
counseling and testing in children with renal tumors. This will include
recommendations on which patients need referral to a clinical geneticist, who
needs genetic testing, which genes should be included with respect to specific
phenotypes and/or tumor types, and how genetic testing should be performed.
Moreover, we will evaluate the impact of extensive genetic testing on patients
and parents. This information will be relevant for the implementation of next
generation sequencing techniques in daily (pediatric oncology) care.

The only physical burden for patients is minimal since venipuncture is only
needed in cases where blood was not previously stored for research. For
children, this will be combined with punctures as part of the cancer treatment
/ follow up. There is a small risk of finding genetic predisposition for
diseases other than cancer, a so called *unsolicited finding*. This risk is
limited as much as possible by the renal cancer predisposition filter, and
patients will be counseled about the risk of unsolicited findings by a clinical
geneticist. The committee for unsolicited findings in the UMCU Genetics
department will assess unsolicited findings for relevance to the
patient/family.

Group relatedness: Pediatric renal tumors are genetically and biologically
different from renal tumors in the adult population. Wilms tumor, the most
common renal tumor in childhood, occurs at a median age of onset of 3.5 years,
and even earlier in patients with a genetic predisposition. In this study, we
are specifically interested in pediatric renal tumors.