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Annals of Oncology Advance Access originally published online on January 15, 2009
Annals of Oncology 2009 20(6):1048-1056; doi:10.1093/annonc/mdn738
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© The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

gastrointestinal tumors

DNA copy number profiles of primary tumors as predictors of response to chemotherapy in advanced colorectal cancer

C. Postma1,{dagger}, M. Koopman2,{dagger}, T. E. Buffart1, P. P. Eijk1, B. Carvalho1, G. J. Peters3, B. Ylstra1, J. H. van Krieken4, C. J. A. Punt2 and G. A. Meijer1,*

1 Department of Pathology, VU University Medical Center, Amsterdam
2 Department of Medical Oncology, Radboud University Nijmegen Medical Center, Nijmegen
3 Department of Medical Oncology, VU University Medical Center, Amsterdam
4 Department of Pathology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

* Correspondence to: Dr G. A. Meijer, Department of Pathology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands. Tel: +31-20-444-4772; Fax: +31-20-444-2964; E-mail: ga.meijer{at}vumc.nl

Background: Colorectal cancer (CRC) is biologically a heterogeneous disease, which may affect response to drug therapy. We investigated the correlation of genome-wide DNA copy number profiles of primary tumors with response to systemic chemotherapy in advanced CRC.

Patients and methods: DNA was isolated from formaldehyde-fixed paraffin-embedded primary tumors of 32 patients with advanced CRC, which were selected based on either a good response (n = 16) or a poor response (n = 16) to first-line combination therapy with capecitabine and irinotecan. High-resolution DNA copy number profiles were obtained by means of 30 K oligonucleotide-based array comparative genomic hybridization (aCGH).

Results: Unsupervised hierarchical cluster analysis of the aCGH data revealed two clusters of 19 and 13 tumors, respectively, and cluster membership showed a significant correlation with response status (P < 0.03). The nonresponders had fewer chromosomal alterations compared with the responders, in particular less losses were found (P < 0.03). Most prominent differences between the two groups were losses of regions 18p11.32–q11.2 (P < 0.02) and 18q12.1–q23 (P < 0.03), which were more frequently observed in responders.

Conclusions: Differences in DNA copy number profiles of primary CRCs are associated with response to systemic combination chemotherapy with capecitabine and irinotecan. Responders overall had more chromosomal alterations, especially loss of chromosome 18.

Key words: array comparative genomic hybridization, chemotherapy, chromosomal alterations, colorectal cancer, predictive marker

{dagger} These authors equally contributed to this paper.

Received for publication August 4, 2008. Revision received November 6, 2008. Accepted for publication November 6, 2008.


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