Research Papers:
Targeted ultradeep sequencing reveals recurrent and mutually exclusive mutations of cancer genes in blastic plasmacytoid dendritic cell neoplasm
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Albrecht Stenzinger1,*, Volker Endris1,*, Nicole Pfarr1, Mindaugas Andrulis1, Korinna Jöhrens2, Frederick Klauschen2, Udo Siebolts3, Thomas Wolf1, Philipp-Sebastian Koch4, Miriam Schulz5, Wolfgang Hartschuh6, Sergij Goerdt4, Jochen K. Lennerz7, Claudia Wickenhauser3, Wolfram Klapper8, Ioannis Anagnostopoulos2,** and Wilko Weichert1,9,**
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.