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Project

SUZ12 as a new modifier gene in NF1-related MPNST development.

Peripheral nerve sheath tumors (PNSTs) are a common feature of neurofibromatosis type 1 (NF1) patients. During life, NF1 individuals have an estimated risk of 8-13% to develop a malignant PNST (MPNST). This risk is even twice as high for the subgroup of patients (5%) with an NF1 microdeletion. Up to now, it is not known which gene, located in the microdeletion region, is causing this increased risk. Preliminary data from our lab and the lab of Prof. Dr. Karen Cichowski (Dr. Thomas De Raedt) suggested a role for the Suppressor of Zeste 12 (SUZ12) gene, located in the NF1 microdeletion region. SUZ12 is part of the polycomb repressive complex 2 (PRC2) which mediates gene silencing through methylation of lysine 27 of histone H3 (H3K27). A study with 28 human NF1-related MPNSTs was set up for genome-wide copy number analysis and mutation analysis of the SUZ12 gene. Significantly more SUZ12 mutations and focal deletions were found in the NF1 microdeletion tumor samples. These data indicated that PRC2 was involved in NF1-related MPNST tumorigenesis, through SUZ12 inactivation in microdeletion patients. MPNST cell lines will be set up from SUZ12+/+, SUZ12+/- and SUZ12-/- MPNSTs to screen for differences in chromatin and histone modification pattern, that can be linked to the SUZ12 status, through chIP-on-chip analysis using an immunoprecipitation with a SUZ12 antibody and the Agilent Human ENCODE chIP-on-chip microarray. Meanwhile, Dr. De Raedt will continu his work on the Nf1+/-/Tp53+/- and Nf1+/-/Suz12+/- mouse model, in order to analyse the effect of the heterozygous SUZ12 status on MPNST development and tumorigenesis in general (time frame, histology, location).
Date:16 Dec 2011 →  15 Dec 2012
Keywords:SUZ12, NF1, MPNST, Sarcoma, Neurofibromatosis type 1, Polycomb repressive complex
Disciplines:Genetics, Systems biology, Molecular and cell biology