Cancer predisposition syndromes (CPS) are increasingly recognized as an important cause of pediatric cancer development. Hitherto in about 10 – 30% of childhood cancers CPSs were identified. This is most likely an underestimation since genetic testing for CPS in children has not yet become routine clinical practice. Signs pointing to predisposition are often missed or not present at young age, thus impeding adequate referral. Recently, the MIPOGG genetic referral tool, an easy to use online and smartphone app decision tool, was developed. However, it has not been prospectively validated in routine clinical practice.
When genetic testing is initiated, often only mutations in known predisposition genes are investigated. It thus currently is unclear what diagnostic approaches and implementation strategies should be used to reveal these predisposed patients efficiently. In addition, little is known about the psychosocial impact of genetic testing for a CPS in children and their family.
This study aims to determine the optimal diagnostic approach for CPS in children with cancer. We will implement and prospectively validate the MIPOGG referral tool. In addition, we will compare the diagnostic yield and efficacy of targeted gene testing based on clinical diagnosis versus whole exome sequencing (WES). We will also explore the added benefit of analyzing the transcriptome to discover non-coding variants and help classify variants of unknown significance (VUS) detected through WES. By measuring the psychosocial impact of CPS testing on the patient and family and exploring facilitators, barriers and challenges in genetic testing, we aim to develop guidelines for CPS testing taking into account the specific needs of the child and the family. This proposal will generate immediate clinical impact, since patients with a CPS will be offered an adjusted surveillance program and risk reducing strategies. Other relatives will be able to opt for predictive testing and counselling.