Genome position and gene amplification.
BACKGROUND
Amplifications, regions of focal high-level copy number change, lead to overexpression of oncogenes or drug resistance genes in tumors. Their presence is often associated with poor prognosis; however, the use of amplification as a mechanism for overexpression of a particular gene in tumors varies. To investigate the influence of genome position on propensity to amplify, we integrated a mutant form of the gene encoding dihydrofolate reductase into different positions in the human genome, challenged cells with methotrexate and then studied the genomic alterations arising in drug resistant cells.


RESULTS
We observed site-specific differences in methotrexate sensitivity, amplicon organization and amplification frequency. One site was uniquely associated with a significantly enhanced propensity to amplify and recurrent amplicon boundaries, possibly implicating a rare folate-sensitive fragile site in initiating amplification. Hierarchical clustering of gene expression patterns and subsequent gene enrichment analysis revealed two clusters differing significantly in expression of MYC target genes independent of integration site.


CONCLUSIONS
These studies suggest that genome context together with the particular challenges to genome stability experienced during the progression to cancer contribute to the propensity to amplify a specific oncogene or drug resistance gene, whereas the overall functional response to drug (or other) challenge may be independent of the genomic location of an oncogene.
Gajduskova
Pavla
P
Cancer Research Institute, University of California San Francisco, San Francisco, CA 94143-0808, USA.
Snijders
Antoine M
AM
Kwek
Serena
S
Roydasgupta
Ritu
R
Fridlyand
Jane
J
Tokuyasu
Taku
T
Pinkel
Daniel
D
Albertson
Donna G
DG
D045744:Cell Line, Tumor; D005784:Gene Amplification / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008727:Methotrexate / Q000494:pharmacology; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics
D013762:Tetrahydrofolate Dehydrogenase; D008727:Methotrexate