High Density custom Agilent 44K CGH array analysis of 7q and TET2 region in myelodysplastic/myeloproliferative neoplasms

Abnormalities of chromosome 7q are common in myeloid malignancies. Agilent CGH arrays targeted to 7q and Affymetrix SNP 6.0 arrays were used to characterise 7q aUPD and deletions. Sample #017 in this data series showed a microdeletion encompassing EZH2. Screening of a total of 614 cases with myeloid disorders revealed 49 monoallelic or biallelic EZH2 mutations in 42 individuals, most commonly myelodysplastic/myeloproliferative neoplasms (27/219; 12%) and myelofibrosis (4/30; 13%). EZH2 encodes the catalytic subunit of the Polycomb repressive complex 2 (PRC2), the highly conserved histone H3 lysine 27 methyltransferase that influences stem cell renewal by epigenetic repression of genes involved in cell fate decisions. EZH2 has oncogenic activity and its overexpression has been causally linked to differentiation blocks in epithelial tumors. Unexpectedly, the mutations we identified resulted in premature chain termination or direct abrogation of histone methyltransferase activity, suggesting that EZH2 acts as a tumor suppressor for myeloid malignancies.