Targeted ultra-deep sequencing reveals recurrent and mutually exclusive mutations of cancer genes in blastic plasmacytoid dendritic cell neoplasm

Abstract

// Albrecht Stenzinger 1,* , Volker Endris 1,* , Nicole Pfarr 1 , Mindaugas Andrulis 1 , Korinna Jöhrens 2 , Frederick Klauschen 2 , Udo Siebolts 3 , Thomas Wolf 1 , Philipp-Sebastian Koch 4 , Miriam Schulz 5 , Wolfgang Hartschuh 6 , Sergij Goerdt 4 , Jochen K. Lennerz 7 , Claudia Wickenhauser 3 , Wolfram Klapper 8 , Ioannis Anagnostopoulos 2,** and Wilko Weichert 1,9,** 1 Institute of Pathology, University Hospital Heidelberg, Germany 2 Institute of Pathology, Charité University Hospital, Berlin, Germany 3 Institute of Pathology, University Hospital Halle and Institute of Pathology, University Hospital Leipzig, Germany 4 Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany 5 German Red Cross Blood Service and Institute for Transfusion Medicine and Immunohematology, Goethe University Medical School, Frankfurt, Germany 6 Department of Dermatology, University Hospital Heidelberg, Germany 7 Institute of Pathology, University of Ulm, Ulm, Germany 8 Department of Pathology, Hematopathology Section and Lymph Node Registry, Christian-Albrechts-University of Kiel, Germany 9 National Center for Tumor Diseases, Heidelberg, Germany 10 Present address: Harvard Medical School, Massachusetts General Hospital, Department of Pathology, Boston, MA, USA * These authors contributed equally to this work ** These authors share last authorship Correspondence: Albrecht Stenzinger , email: // Ioannis Anagnostopoulos, email: // Keywords : blastic plasmacytoid dendritic cell neoplasm, BPDCN, recurrent mutations, mutually exclusive mutations, next generation sequencing, ATM, KRAS, NRAS, CDKN2A Received : May 20, 2014 Accepted : July 15, 2014 Published : July 16, 2014 Abstract Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare haematopoietic malignancy characterized by dismal prognosis and overall poor therapeutic response. Since the biology of BPDCN is barely understood, our study aims to shed light on the genetic make-up of these highly malignant tumors. Using targeted high-coverage massive parallel sequencing, we investigated 50 common cancer genes in 33 BPDCN samples. We detected point mutations in NRAS (27.3% of cases), ATM (21.2%), MET, KRAS, IDH2, KIT (9.1% each), APC and RB1 (6.1% each), as well as in VHL, BRAF, MLH1, TP53 and RET (3% each). Moreover, NRAS, KRAS and ATM mutations were found to be mutually exclusive and we observed recurrent mutations in NRAS, IDH2, APC and ATM. CDKN2A deletions were detected in 27.3% of the cases followed by deletions of RB1 (9.1%), PTEN and TP53 (3% each). The mutual exclusive distribution of some mutations may point to different subgroups of BPDCN whose biological significance remains to be explored.