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Mardi 25 Septembre 2018
De 11h à 12h
Centre de Recherche - Paris - Amphithéâtre Antoine Lacassagne

Hereditary predisposition to childhood brain tumors – an underappreciated challenge?

It has been well established that pathogenic germline mutations in genes like TP53, PTCH1, SUFU, APC, NF1, SMARCB1, SMARCA4, BRCA2 and the MMR genes are associated with an increased incidence of brain tumors. Most of them are associated with a specific type of brain tumor. It has been estimated that as many as 7-10% of all pediatric tumors (and brain tumors) are based on a highly penetrant germline mutation. However, this might still be an under-appreciation of this enormous clinical and scientific challenge. We have recently shown that ~20% of SHH-driven medulloblastomas have an underlying germline mutation in TP53, PTCH1, SUFU, BRCA2 or PALB2 when only focusing on known cancer predisposition genes. When then doing an unbiased genome-wide screen investigating all genes for truncating germline variants that are exceedingly rare in the normal population, we were able to identify another highly prevalent medulloblastoma predisposition gene, which we are currently futher analyzing in terms of co-occuring mutations and functional impact. This new finding increases the rate of SHH medulloblastomas with a clear germline predisposition to ~30%. It is very likely that similar findings will also further increase this proportion in other pediatric cancers. We are trying to address this question by a genome-wide pediatric cancer germline analysis performed on all publicly available data.


Pr Stefan Pfister


Mme Carole Drique
Assistante gestionnaire U830

Invité(e)(s) par

Dr Olivier Delattre
Directeur U830

En bref

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2.) Pajtler KW, Witt H, Sill M et al., …and Kool, M.*, Pfister, S.M.* (2015). Molecular Classification of Ependymal Tumors across All CNS Compartments, Histopathological Grades, and Age Groups. Cancer Cell. 27(5):728-43.
3.) Northcott, P. et al., …and Peter Lichter, P.*, Korbel, J.O.*, Wechsler-Reya, R*, Pfister, S.M.* (2014) Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Nature 511(7510):428-34.
4.) Hovestadt, V. and Jones, D.T.W. et al., …,and Radlwimmer, B.*, Pfister, S.M.* ,Lichter, P.* (2014). Decoding the regulatory landscape of medulloblastoma using DNA methylation profiling. Nature 510(7506):537-41.
5.) Kool M et al.,…,and Wechsler-Reya, R.J.*, Lichter, P.*, Pfister, S.M*. (2014). Genome Sequencing of SHH Medulloblastoma Predicts Genotype-Related Response to Smoothened Inhibition. Cancer Cell 25(3):393-405.
6.) Bender, S., Tang, Y., Lindroth, A.M., et al., …and Plass, C., Cho, Y.J., Pfister, S.M. (2013). Reduced H3K27me3 and DNA Hypomethylation Are Major Drivers of Gene Expression in K27M Mutant Pediatric High-Grade Gliomas. Cancer Cell 24(5):660-72.
7.) Jones, D.T.W. et al., … and Pfister, S.M.* (2013) Recurrent FGFR1 hotspot mutations represent a novel therapeutic target in childhood astrocytoma. Nature Genetics 45(8):927-32.
8.) Sturm, D., Witt, H., and Hovestadt, V. et al.,…, and Plass C*, Jabado N* & Pfister, S.M.* (2012). Hotspot Mutations in H3F3A and IDH1 Define Distinct

9.) Rausch, T. etal., … and Lichter, P.*, Pfister, S.M.*, Korbel, J.O.* (2012) Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations. Cell 148, 59-71.
10.) Schwartzentruber, J.*, Korshunov, A.*, Liu, X.Y.* et al., …, and Majewski, J.*, Pfister, S.M.*, Jabado, N.* (2012). Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482(7384):226-31Epigenetic and Biological Subgroups of Glioblastoma. Cancer Cell 22(4):425-37.