MEDB-01. Management of the risk of medulloblastoma associated to familial adenomatous polyposis and dysregulated Wnt signalosome

APC is the key gene of the familial adenomatous polyposis (FAP). This tumor suppressor gene functions by negatively regulating the β-catenin protein and the majority of APC mutations disrupt the β-catenin degradation complex signalosome leading to the activation of the canonical Wnt pathway. Pathogenic APC mutations were reported in association to medulloblastoma. In this study, we report rare mutations of the APC gene detected in Tunisian families from the governorate of Sfax presenting clinically with various digestive and extra-digestive manifestations. Our goal was to assess the oncogenic risks encountered by our pediatric carriers to offer an accurate genetic counselling, particularly at the neurologic level. Molecular investigation of all members of two families was conducted, using bidirectional sequencing of all 15 exons of the APC gene. A phenotype-genotype correlation was conducted to elucidate the mutational pathophysiological mechanism. Two rare mutations were revealed in our familial study. The first mutation was located at exon 13 and was a missense mutation at codon 1690. The second mutation was a deletion identified at codon 4652 in exon 15. The mutations resulted both in truncated gene products. Clinical manifestations closely depending on the position of the mutation were respectively colic polyposis for the first mutation and soft tissue fibromatous tumors for the second. The localization of the APC mutations allows better targeting of surveillance for clinical manifestations that may be included in FAP. Mutations that remove the Axin-binding sites, as is the case for the first mutation, lead to severe clinical pictures whereas mutations that retain one or two of the Axin binding sites are associated with other features such as desmoid tumors. The risk of the Wnt- medulloblastoma subtype, higher among patients with FAP should be considered with a more awareness of signs and symptoms related to CNS tumors in the FAP context.