21B. Tumor-based molecular signatures of childhood cancer predisposition

Recognition of cancer susceptibility in children is of high clinical significance to provide optimized care for children during and after treatment. Syndrome diagnostics can be challenging because of phenotypic variability, germline mosaicism, undiscovered genes and loci underlying susceptibility, and the involvement of germline aberrations that require advanced diagnostics. Comprehensive knowledge of molecular tumour characteristics that are typical for specific cancer predisposition syndromes may circumvent many of these challenges and, thereby, support recognition of this group of patients. Furthermore, knowledge of these syndrome-specific tumour characteristics can improve our understanding of tumour development and reveal potential strategies for intervention.

In the current project we aim to unravel the tumour-based molecular signatures for several paediatric tumour types that occur in the context of cancer predisposition syndromes, particularly those that present without additional syndromic features, including but not limited to, Wilms tumor predisposition syndromes, Li Fraumeni syndrome, Neurofibromatosis type 1, and DICER1 syndrome. We have the following three objectives:

1. Collect available and generate new genome-wide transcriptome and methylome profiling data from tumours of children with cancer predisposition syndromes to identify differentially expressed genes and differentially methylated regions that hallmark tumours that arise in the context of a cancer predisposition syndrome.
2. Develop classifiers based on transcriptome- and methylome-based somatic signatures that facilitate the recognition of childhood cancer predisposition syndromes and validate these classifiers on independent cohorts.
3. Perform a comprehensive analysis of cases for which no syndrome has been diagnosed but that share the tumour-based molecular features identified in objectives 1 and/or 2 to identify novel causes of predisposition.

If successful, this project will result in strategies to improve the early identification of pediatric patients with high suspicion of a specific cancer predisposition syndrome, irrespective of the presence of syndromic features, thereby contributing to better care and surveillance for these children.