Genome position and gene amplification

Pavla Gajduskova, Antoine M. Snijders, Serena Kwek, Ritu Roydasgupta, Jane Fridlyand, Taku Tokuyasu, Daniel Pinkel, Donna Albertson

Research output: Contribution to journalArticle

Abstract

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. Conclusion: 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.

Original languageEnglish (US)
Article numberR120
JournalGenome Biology
Volume8
Issue number6
DOIs
StatePublished - Jun 21 2007

Fingerprint

gene amplification
Gene Amplification
amplification
genome
Genome
oncogenes
gene
methotrexate
Oncogenes
Genes
drug resistance
genes
neoplasms
Drug Resistance
Methotrexate
tumor
dihydrofolate reductase
genomics
drug
drugs

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Cell Biology
  • Genetics

Cite this

Gajduskova, P., Snijders, A. M., Kwek, S., Roydasgupta, R., Fridlyand, J., Tokuyasu, T., ... Albertson, D. (2007). Genome position and gene amplification. Genome Biology, 8(6), [R120]. https://doi.org/10.1186/gb-2007-8-6-r120

Genome position and gene amplification. / Gajduskova, Pavla; Snijders, Antoine M.; Kwek, Serena; Roydasgupta, Ritu; Fridlyand, Jane; Tokuyasu, Taku; Pinkel, Daniel; Albertson, Donna.

In: Genome Biology, Vol. 8, No. 6, R120, 21.06.2007.

Research output: Contribution to journalArticle

Gajduskova, P, Snijders, AM, Kwek, S, Roydasgupta, R, Fridlyand, J, Tokuyasu, T, Pinkel, D & Albertson, D 2007, 'Genome position and gene amplification', Genome Biology, vol. 8, no. 6, R120. https://doi.org/10.1186/gb-2007-8-6-r120
Gajduskova P, Snijders AM, Kwek S, Roydasgupta R, Fridlyand J, Tokuyasu T et al. Genome position and gene amplification. Genome Biology. 2007 Jun 21;8(6). R120. https://doi.org/10.1186/gb-2007-8-6-r120
Gajduskova, Pavla ; Snijders, Antoine M. ; Kwek, Serena ; Roydasgupta, Ritu ; Fridlyand, Jane ; Tokuyasu, Taku ; Pinkel, Daniel ; Albertson, Donna. / Genome position and gene amplification. In: Genome Biology. 2007 ; Vol. 8, No. 6.
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