Project Funding Details

Alterations of imprinted gene expression and/or methylation are frequently found in human cancers and congenital imprinting disorders, and mouse models have given support to the hypothesis that loss of imprinting (LOI) is an early event predisposing cells to tumorigenesis. However, imprinting deregulation is a complex phenomenon that can affect single or multiple loci and be associated with gene activation or gene downregulation, and establishing its role in cancer development requires further investigation. (Epi)genetic abnormalities in the imprinted gene cluster of chromosome 11p15.5 are frequently found in the tumor-associated Beckwith-Wiedemann syndrome (BWS) and both syndromic and non-syndromic Wilms tumor (WT). A subset of BWS patients display multi-locus imprinting disturbance (MLID), thus also involving loci other than those at 11p15.5. The frequency of MLID in WT is unknown. Genetic variants occurring in cis or in trans with imprinting disturbances have been demonstrated in some BWS and WT cases. Maternal-effect, germline or somatic genetic variants may cause or predispose to multi-locus or single-locus imprinting deregulation and impact the phenotype of a large number of BWS and WT cases. This project aims to define the genetic variants and molecular mechanisms underlying imprinting disturbances in BWS and WT, and to determine their relevance for patient stratification and follow-up. Methylation imprinting in BWS and WT will be preliminary investigated by MS-MLPA and pyrosequencing and subsequently by interrogating whole-genome methylation-arrays. Whole-genome SNVs and CNVs in maternal, germline and tumor-DNAs that are associated with imprinting alterations in BWS and WT cases will be determined by employing exome-seq and high-resolution SNP-array analyses. Global and allele-specific imprinted expression will be assessed by RNAseq. (Epi)genotype will be correlated with clinical data in a large cohort of cases, and penetrance and recurrence risk of genetic variants will be investigated. i. Whole-genome methylation imprinting signatures in BWS and WT; ii. identification of genetic variants causing or predisposing to imprinting dysregulation in BWS and WT; iii. Relationship between methylation imprinting and imprinted gene expression in WT; iv. Impact of imprinting disturbances on BWS and WT clinical phenotypes. This project will: i. enhance our understanding on imprinting disturbances in BWS and WT by determining their frequency and extent, and relationship between methylation and expression imprinting; ii. improve molecular diagnosis and patient stratification by defining whole genome methylation imprinting signatures; iii. impact the management of patients by determining predisposing genetic variants, their penetrance and associated recurrence risks, and epigenotype-phenotype correlations.