title: Isochromosome breakpoints on 17p in medulloblastoma are flanked by different classes of DNA sequence repeats.
abstract: Medulloblastoma is a highly malignant embryonal tumor of the cerebellum that accounts for 20%-25% of all intracranial pediatric tumors. The most frequent chromosomal rearrangement in medulloblastoma is isochromosome 17, or i(17q). Its frequency suggests that it serves an important role in tumor pathogenesis, possibly mediated by the disruption or permanent activation of a gene at the breakpoint. To address this question, we performed a detailed analysis of chromosome 17 DNA copy number from 18 medulloblastomas previously shown to carry an apparent i(17q). We identified two breakpoint regions, one well within band 17p11.2 (n = 16) and a second within the pericentromeric region (n = 2). To map the breakpoints more precisely, we constructed a tiling-path matrix-CGH array covering chromosomal band 17p11.2 to the centromere and utilized it to delineate two small breakpoint intervals mapping at Mb 19.0 and 21.7 in seven of the medulloblastomas and in nine hematological neoplasias with i(17q). The former interval contains two breakpoint clusters that each colocalize with a pair of head-to-head inverted DNA sequence repeats, and the latter maps close to a region of alpha-satellite repeats. No consensus coding sequence localizes in these regions. Together, these data strongly suggest that the effects of i(17q) in medulloblastoma are mediated by gene-dosage effects of genes on 17p or 17q rather than by the disruption or deregulation of a "breakpoint" gene. Furthermore, we identified artifacts introduced in DNA copy number data by cross-hybridization of low-copy repeat sequences and discuss the challenge these can pose in the interpretation of diagnostic microarrays.
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Mendrzyk
authors.forename: Andrey
authors.initials: A
authors.lastname: Korshunov
authors.forename: Grischa
authors.initials: G
authors.lastname: Toedt
authors.forename: Frank
authors.initials: F
authors.lastname: Schwarz
authors.forename: Bernhard
authors.initials: B
authors.lastname: Korn
authors.forename: Stefan
authors.initials: S
authors.lastname: Joos
authors.forename: Andreas
authors.initials: A
authors.lastname: Hochhaus
authors.forename: Claudia
authors.initials: C
authors.lastname: Schoch
authors.forename: Peter
authors.initials: P
authors.lastname: Lichter
authors.forename: Bernhard
authors.initials: B
authors.lastname: Radlwimmer
mesh_terms: D002528:Cerebellar Neoplasms / Q000235:genetics*; D019457:Chromosome Breakage; D002886:Chromosomes, Human, Pair 17; D019337:Hematologic Neoplasms / Q000235:genetics; D006801:Humans; D018404:Isochromosomes; D008527:Medulloblastoma / Q000175:diagnosis / Q000235:genetics*; D009693:Nucleic Acid Hybridization; D020161:Physical Chromosome Mapping; D012091:Repetitive Sequences, Nucleic Acid