Genome Position and Gene Amplification

Overview

Journal Genome Biol

Specialties Biology
Genetics

Date 2007 Jun 23

PMID 17584934

Citations 13

Authors

Pavla Gajduskova

Antoine M Snijders

Serena Kwek

Ritu Roydasgupta

Jane Fridlyand

Taku Tokuyasu

Daniel Pinkel

Donna G Albertson

Affiliations

Soon will be listed here.

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.

Citing Articles

Recent advances and application of whole genome amplification in molecular diagnosis and medicine.

Wang X, Liu Y, Liu H, Pan W, Ren J, Zheng X MedComm (2020). 2022; 3(1):e116.

PMID: 35281794 PMC: 8906466. DOI: 10.1002/mco2.116.

Systems Biology Approach Identifies Prognostic Signatures of Poor Overall Survival and Guides the Prioritization of Novel BET-CHK1 Combination Therapy for Osteosarcoma.

Pandya P, Cheng L, Saadatzadeh M, Bijangi-Vishehsaraei K, Tang S, Sinn A Cancers (Basel). 2020; 12(9).

PMID: 32859084 PMC: 7564419. DOI: 10.3390/cancers12092426.

Complex chromosomal neighborhood effects determine the adaptive potential of a gene under selection.

Steinrueck M, Guet C Elife. 2017; 6.

PMID: 28738969 PMC: 5526668. DOI: 10.7554/eLife.25100.

Engineering targeted chromosomal amplifications in human breast epithelial cells.

Springer S, Yi K, Park J, Rajpurohit A, Price A, Lauring J Breast Cancer Res Treat. 2015; 152(2):313-21.

PMID: 26099605 PMC: 4491111. DOI: 10.1007/s10549-015-3468-2.

Genomic organization and evolution of double minutes/homogeneously staining regions with MYC amplification in human cancer.

LAbbate A, Macchia G, DAddabbo P, Lonoce A, Tolomeo D, Trombetta D Nucleic Acids Res. 2014; 42(14):9131-45.

PMID: 25034695 PMC: 4132716. DOI: 10.1093/nar/gku590.

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