AbstractsBiology & Animal Science

Primary brain tumors are the most common group of solid cancers in the pediatric years and are the primary source of cancer related mortality and morbidity in children. They are segregated into gliomas and embryonal tumors which are further subdivided by the World Health Organization into pathological groups and graded according to their degree of malignancy. To date, both gliomas and embryonal tumors are diagnosed and treated based on this histopathological classification, yet several molecular findings indicate this classification is obsolete and that this may partly account for the dismal outcome seen for some of the high-grade tumours. To improve molecular diagnosis and gain insight into novel targets, we investigated using genetic, molecular and biochemical tools two groups of pediatric high-grade brain tumors, namely from the glioma lineage anaplastic astrocytoma (AA) and glioblastoma (GBM), and from the embryonal tumors lineage the embryonal tumors with multilayered rosettes (ETMR). We initially investigated the effects of Y-Box Protein 1 (YB1) on translation of astrocytic cells, a gene previously found by our lab to be overexpressed in pediatric GBM. Overexpression of YB1 led to altered expression in astrocytomas. In pediatric GBM cell lines, it led to the dysregulation of a core chromatin gene, HIST1H1A highlighting a possible epigenetic role for YB1, and uncovered a set of new prospective targets of YB1 with potential role in astrocytoma genesis. Our subsequent investigation of AA and GBM using integrative high throughput analyses indicated that this grade distinction is arbitrary as pediatric anaplastic astrocytoma (pAA, grade III) are molecularly similar to pediatric glioblastoma (pGBM, grade IV) and that tumors segregate based on the underlying genetic mutations they carry. Hence, we propose that future diagnoses and therapies be based on patho-molecular features rather than the underlying tumor grade as per the current WHO classification. Our studies of a newly described embryonal entity, ETMR, identify a novel fusion between TTYH1 and the C19MC microRNA cluster in all samples. This characteristic TTYH1-C19MC fusion in these tumors leads to extremely high expression levels of members of the C19MC microRNA cluster in all ETMR investigated, and subsequently to de-repression of the expression of an embryonic brain-specific isoform of DNMT3B, a de novo DNA methyltransferase. Re-awakening or aberrant maintenance of an embryonic pathway in these tumors affects the epigenome and is possibly at the origin of these intractable tumors. This work as a whole has provided novel insight into three different pediatric high-grade brain tumors, and has facilitated the discovery of novel markers and underlying mechanisms which can now be used to improve the diagnoses and treatment modalities of patients with these devastating cancers. Les tumeurs cérébrales primitives appartiennent au groupe le plus commun de tumeurs solides rencontrées en pédiatrie. C'est la principale cause de mortalité et de morbidité liée…