A role for common fragile site induction in amplification of human oncogenes.
Oncogene amplification is an important process in human tumorigenesis, but its underlying mechanism is currently unknown. Cytogenetic analysis indicates that amplification of drug-selected genes in rodent cells is driven by recurrent breaks within chromosomal common fragile sites (CFSs), via the breakage-fusion-bridge (BFB) mechanism. Here we show that BFB cycles drive the intrachromosomal amplification of the MET oncogene in a human gastric carcinoma. Our molecular evidence includes a "ladder-like" structure and inverted repeat organization of the MET amplicons. Furthermore, we show that the breakpoints, setting the centromeric amplicon boundaries, are within the CFS FRA7G region. Upon replication stress, this region showed perturbed chromatin organization, predisposing it to breakage. Thus, in vivo induction of CFSs can play an important role in human oncogenesis.
Hellman
Asaf
A
Department of Genetics, The Life Sciences Institute, The Hebrew University, Jerusalem 91904, Israel.
Zlotorynski
Eitan
E
Scherer
Stephen W
SW
Cheung
Joseph
J
Vincent
John B
JB
Smith
David I
DI
Trakhtenbrot
Luba
L
Kerem
Batsheva
B
D002503:Centromere / Q000502:physiology; D002843:Chromatin / Q000235:genetics; D002869:Chromosome Aberrations; D025063:Chromosome Disorders; D043283:Chromosome Fragile Sites; D002873:Chromosome Fragility / Q000235:genetics*; D005784:Gene Amplification / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D009857:Oncogenes / Q000235:genetics*; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism; D012091:Repetitive Sequences, Nucleic Acid; D013274:Stomach Neoplasms / Q000235:genetics*; D014407:Tumor Cells, Cultured
D002843:Chromatin; D019859:Proto-Oncogene Proteins c-met