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A role for common fragile site induction in amplification of human oncogenes
Asaf Hellman1, Eitan Zlotorynski, Stephen W Scherer
1Department of Genetics, The Life Sciences Institute, The Hebrew University, Jerusalem 91904, Israel.
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.
Insights
Breakage-fusion-bridge cycles drive oncogene amplification in human cancers. This study reveals how common fragile sites contribute to MET oncogene amplification in gastric cancer.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Oncogene amplification is a key driver of human tumorigenesis, yet its mechanisms remain unclear.
- The breakage-fusion-bridge (BFB) mechanism is implicated in gene amplification, particularly in response to drug selection in rodent cells.
- Common fragile sites (CFSs) are regions prone to breakage during replication stress and are associated with chromosomal instability.
Purpose of the Study:
- To investigate the mechanism of oncogene amplification in human cancer.
- To determine if the BFB mechanism and CFSs are involved in the amplification of the MET oncogene in human gastric carcinoma.
- To elucidate the role of replication stress at CFSs in driving oncogene amplification.
Main Methods:
- Molecular and cytogenetic analysis of MET oncogene amplicons in human gastric carcinoma.
- Characterization of amplicon structure, including "ladder-like" patterns and inverted repeats.
- Breakpoint mapping to identify the chromosomal locations and association with CFSs, specifically FRA7G.
- Analysis of chromatin organization and replication stress response at CFS regions.
Main Results:
- BFB cycles were identified as the driving mechanism for intrachromosomal amplification of the MET oncogene in human gastric carcinoma.
- Molecular evidence, including a "ladder-like" structure and inverted repeat organization, supports the BFB model for MET amplicon formation.
- Amplicon breakpoints were localized to the FRA7G common fragile site region.
- Replication stress induced perturbed chromatin organization at FRA7G, predisposing it to breakage.
Conclusions:
- BFB cycles are a significant mechanism for oncogene amplification in human cancers.
- Common fragile sites, like FRA7G, are critical genomic locations that can be induced by replication stress to drive oncogene amplification.
- The findings highlight the role of CFSs in human oncogenesis through the induction of gene amplification.