Anna Dolnik1, Julia C. Engelmann2, Maren Scharfenberger-Schmeer3, Julian Mauch1, Sabine Kelkenberg-Schade3, Berit Haldemann3, Tamara Fries3, Jan Krönke1, Michael W.M. Kühn1, Peter Paschka1, Sabine Kayser1, Stephan Wolf3, Verena I. Gaidzik1, Richard F. Schlenk1, Frank G. Rücker1, Hartmut Döhner1, Claudio Lottaz2, Konstanze Döhner1, Lars Bullinger1
1Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany
2Statistical Bioinformatics, Institute for Functional Genomics, University of Regensburg, Regensburg, Germany
3Genomics and Proteomics Core Facilities, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany
Tóm tắt
Abstract
Acute myeloid leukemia (AML) is characterized by molecular heterogeneity. As commonly altered genomic regions point to candidate genes involved in leukemogenesis, we used microarray-based comparative genomic hybridization and single nucleotide polymorphism profiling data of 391 AML cases to further narrow down genomic regions of interest. Targeted resequencing of 1000 genes located in the critical regions was performed in a representative cohort of 50 AML samples comprising all major cytogenetic subgroups. We identified 120 missense/nonsense mutations as well as 60 insertions/deletions affecting 73 different genes (∼ 3.6 tumor-specific aberrations/AML). While most of the newly identified alterations were nonrecurrent, we observed an enrichment of mutations affecting genes involved in epigenetic regulation including known candidates like TET2, TET1, DNMT3A, and DNMT1, as well as mutations in the histone methyltransferases NSD1, EZH2, and MLL3. Furthermore, we found mutations in the splicing factor SFPQ and in the nonclassic regulators of mRNA processing CTCF and RAD21. These splicing-related mutations affected 10% of AML patients in a mutually exclusive manner. In conclusion, we could identify a large number of alterations in genes involved in aberrant splicing and epigenetic regulation in genomic regions commonly altered in AML, highlighting their important role in the molecular pathogenesis of AML.
