A role for common fragile site induction in amplification of human oncogenes

Asaf Hellman, Eitan Zlotorynski, Stephen W. Scherer, Joseph Cheung, John B. Vincent, David I. Smith, Luba Trakhtenbrot, Batsheva Kerem

Research output: Contribution to journalArticlepeer-review

216 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)89-97
Number of pages9
JournalCancer cell
Volume1
Issue number1
DOIs
StatePublished - Feb 2002

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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