Digital karyotyping identifies thymidylate synthase amplification as a mechanism of resistance to 5-fluorouracil in metastatic colorectal cancer patients

Tian Li Wang, Luis A. Diaz, Katharine Romans, Alberto Bardelli, Saurabh Saha, Gennaro Galizia, Michael Choti, Ross Donehower, Giovanni Parmigiani, Ie Ming Shih, Christine Iacobuzio-Donahue, Kenneth W. Kinzler, Bert Vogelstein, Christoph Lengauer, Victor E. Velculescu

Research output: Contribution to journalArticle

Abstract

Resistance to chemotherapy is a major cause of mortality in advanced cancer patients. In this study, digital karyotyping was used to search for genomic alterations in liver metastases that were clinically resistant to 5-fluorouracil (5-FU). In two of four patients, we identified amplification of an ≈-100-kb region on 18p11.32 that was of particular interest because it contained the gene encoding thymidylate synthase (TYMS), a molecular target of 5-FU. Analysis of TYMS by fluorescence in situ hybridization identified TYMS gene amplification in 23% of 31 5-FU-treated cancers, whereas no amplification was observed in metastases of patients that had not been treated with 5-FU. Patients with metastases containing TYMS amplification had a substantially shorter median survival (329 days) than those without amplification (1,021 days, P

Original languageEnglish
Pages (from-to)3089-3094
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number9
DOIs
Publication statusPublished - Mar 2 2004

ASJC Scopus subject areas

  • Genetics
  • General

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    Wang, T. L., Diaz, L. A., Romans, K., Bardelli, A., Saha, S., Galizia, G., Choti, M., Donehower, R., Parmigiani, G., Shih, I. M., Iacobuzio-Donahue, C., Kinzler, K. W., Vogelstein, B., Lengauer, C., & Velculescu, V. E. (2004). Digital karyotyping identifies thymidylate synthase amplification as a mechanism of resistance to 5-fluorouracil in metastatic colorectal cancer patients. Proceedings of the National Academy of Sciences of the United States of America, 101(9), 3089-3094. https://doi.org/10.1073/pnas.0308716101