Novel gene rearrangements in transformed breast cells identified by high-resolution breakpoint analysis of chromosomal aberrations.
Chromosomal copy number alterations and chromosomal rearrangements are frequent mutations in human cancer. Unlike copy number alterations, little is known about the role and occurrence of chromosomal rearrangements in breast cancer. This may be due to the fact that chromosome-based breakpoint analysis is widely restricted to cultured cells. In order to identify gene rearrangements in breast cancer, we studied the chromosomal breakpoints in radiation-transformed epithelial breast cell lines using a high-resolution array-based approach using 1 Mb bacterial artificial chromosome (BAC) arrays. The breakpoints were further narrowed down by fluorescence in situ hybridisation (FISH) with clones from the 32 k BAC library. The analysis of the cell lines B42-11 and B42-16 revealed rearrangements of chromosomes 7, 8, 10 and 12. We identified the genes Has2, Grid1, Ret, Cpm, Tbx3, Tbx5, Tuba1a, Wnt1 and Arf3 within the breakpoint regions. Quantitative RT-PCR showed a deregulated expression of all of these candidate genes except for Tbx5 and Tbx3. This is the first study demonstrating gene rearrangements and their deregulated mRNA expression in radiation-transformed breast cells. Since the gene rearrangements occurred in the transformed and tumourigenic cell lines only, it is likely that these were generated in conjunction with malignant transformation of the epithelial breast cells and therefore might reflect early molecular events in breast carcinogenesis. Initial studies indicate that these gene alterations are also found in sporadic breast cancers.
Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Department of Radiation Cytogenetics, Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany.
Kristian
K
Unger
Johannes
J
Wienberg
Andrew
A
Riches
Ludwig
L
Hieber
Axel
A
Walch
Andreas
A
Brown
Patricia C M
PC
O'Brien
Cäcilia
C
Briscoe
Lindsey
L
Gray
Elke
E
Rodriguez
Gerhard
G
Jackl
Jeroen
J
Knijnenburg
Giovanni
G
Tallini
Malcolm
M
Ferguson-Smith
Horst
H
Zitzelsberger
D000818:Animals; D001940:Breast / Q000528:radiation effects / Q000648:ultrastructure*; D001943:Breast Neoplasms / Q000235:genetics* / Q000648:ultrastructure; D002461:Cell Line, Transformed / Q000648:ultrastructure; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000528:radiation effects; D002869:Chromosome Aberrations; D020223:Chromosome Painting; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics; D002877:Chromosomes, Human / Q000528:radiation effects* / Q000648:ultrastructure; D055028:Comparative Genomic Hybridization; D004847:Epithelial Cells / Q000378:metabolism / Q000528:radiation effects / Q000648:ultrastructure; D005260:Female; D005720:Gamma Rays / Q000009:adverse effects; D018628:Gene Dosage; D015723:Gene Library; D052138:Genes, Neoplasm; D056726:Genetic Association Studies; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis / Q000235:genetics* / Q000302:isolation & purification; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D032681:Spectral Karyotyping
D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger