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

doi:10.1016/S1535-6108(02)00017-X

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

248 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 language	English
Pages (from-to)	89-97
Number of pages	9
Journal	Cancer Cell
Volume	1
Issue number	1
DOIs	https://doi.org/10.1016/S1535-6108(02)00017-X
State	Published - Feb 2002

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10.1016/S1535-6108(02)00017-X

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title = "A role for common fragile site induction in amplification of human oncogenes",

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.",

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AU - Hellman, Asaf

AU - Zlotorynski, Eitan

AU - Scherer, Stephen W.

AU - Cheung, Joseph

AU - Vincent, John B.

AU - Smith, David I.

AU - Trakhtenbrot, Luba

AU - Kerem, Batsheva

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AB - 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.

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

Abstract

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