title: Alterations of the cell-cycle inhibitors p27(KIP1) and p16(INK4a) are frequent in blastic plasmacytoid dendritic cell neoplasms.
abstract: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, clinically aggressive malignancy with a median survival of 12-14 months. To identify pathogenetic relevant genomic aberrations and molecular targets for therapy, we analyzed skin biopsy samples obtained from 14 patients using high-resolution array-based comparative genomic hybridization and immunostaining. Losses of chromosomes 9, 12, 13, and 15 were detected most frequently. Loss of the CDKN1B locus was the most common finding and was detected in 64% of tumors. In all but one case, the dose-dependent haploinsufficient cell-cycle inhibitor p27(KIP1), encoded by CDKN1B, was weakly expressed in the nuclei of tumor cells. Losses of the CDKN2A-ARF-CDKN2B locus occurred in 50% of patients, and in one case a distinct biallelic loss was identified. The cell-cycle inhibitor p16(INK4a), which is encoded by CDKN2A, was not expressed in tumor cells, suggesting a complete loss of function. Loss of chromosome 13, including the RB1 gene, was observed in 43% of tumors. These results imply that alterations of the cell-cycle checkpoint controlling proteins p27(KIP1), p16(INK4a), and RB1 may exert a profound effect in malignant transformation in BPDCN. The elucidation of the affected pathways may guide the development of new treatments specifically designed for this aggressive disease entity.
authors.affiliation: Research Unit of Dermatopathology, Department of Dermatology, Medical University of Graz, Graz, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wiesner
authors.forename: Anna C
authors.initials: AC
authors.lastname: Obenauf
authors.forename: Carlo
authors.initials: C
authors.lastname: Cota
authors.forename: Isabella
authors.initials: I
authors.lastname: Fried
authors.forename: Michael R
authors.initials: MR
authors.lastname: Speicher
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Cerroni
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002869:Chromosome Aberrations; D055028:Comparative Genomic Hybridization; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003713:Dendritic Cells / Q000473:pathology* / Q000502:physiology; D005260:Female; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016160:Retinoblastoma Protein / Q000235:genetics; D012878:Skin Neoplasms / Q000473:pathology* / Q000503:physiopathology
chemical_list: C436291:CDKN1B protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D047908:Intracellular Signaling Peptides and Proteins; D016160:Retinoblastoma Protein; D050760:Cyclin-Dependent Kinase Inhibitor p27