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Shaping of tumor and drug-resistant genomes by instability and selection

Oncogene volume 22, pages 4370–4379 (2003)Cite this article

Abstract

Tumors with defects in mismatch repair (MMR) show fewer chromosomal changes by cytogenetic analyses than most solid tumors, suggesting that a greater proportion of the alterations required for malignancy occur in genes with nucleotide sequences susceptible to errors normally corrected by MMR. Here, we used genome-wide microarray comparative genomic hybridization to carry out a higher resolution evaluation of the effect of MMR competence on genomic alterations occurring in 20 cell lines and to determine if characteristic aberrations arise in MMR-proficient and -deficient HCT116 cells undergoing selection for methotrexate resistance. We observed different spectra of aberrations in MMR-proficient compared to -deficient cell lines, as well as among cell lines with different types of MMR-deficiency. We also observed different genetic routes to drug resistance. Resistant MMR-deficient cells most frequently displayed no copy number alterations (16/29 cell pools), whereas all MMR-proficient cells had unique abnormalities involving chromosome 5, including amplicons centered on the target gene, DHFR and/or a neighboring novel locus (7/13 pools). These observations support the concept that tumor genomes are shaped by selection for alterations that promote survival and growth advantage, as well as by the particular dysfunctions in genes responsible for maintenance of genetic integrity.

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Acknowledgements

We thank M Koi and CR Boland for providing HCT116+chr3 cells, N Nowak and J Conroy for providing clones from the RP11 library and T Paulson and G Wahl for sharing protocols and cells. We thank S Blackwood, N Brown, G Hamilton, B Huey, S Kwek and A Matthäi for their participation in discussions and array production, and K Kimura and the UCSF Cancer Center Bioinformatics Core for microarray database support. This work was supported by NIH Grants CA94407 and CA83040.

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Authors and Affiliations

  1. Cancer Research Institute, University of California San Francisco, San Francisco, CA, USA

    Antoine M Snijders, Jane Fridlyand, Dorus A Mans, Ajay N Jain & Donna G Albertson

  2. Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA

    Richard Segraves, Ajay N Jain, Daniel Pinkel & Donna G Albertson

  3. Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA

    Antoine M Snijders, Jane Fridlyand, Dorus A Mans, Richard Segraves, Ajay N Jain, Daniel Pinkel & Donna G Albertson

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  1. Antoine M Snijders
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Correspondence to Donna G Albertson.

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Snijders, A., Fridlyand, J., Mans, D. et al. Shaping of tumor and drug-resistant genomes by instability and selection. Oncogene 22, 4370–4379 (2003). https://doi.org/10.1038/sj.onc.1206482

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