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

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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 <0.01). These data suggest that genetic amplification of TYMS is a major mechanism of 5-FU resistance in vivo and have important implications for the management of colorectal cancer patients with recurrent disease.

Original languageEnglish (US)
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
StatePublished - Mar 2 2004

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Karyotyping
Thymidylate Synthase
Fluorouracil
Colorectal Neoplasms
Neoplasm Metastasis
Gene Amplification
Fluorescence In Situ Hybridization
Neoplasms
Drug Therapy
Survival
Mortality
Liver
Genes

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Digital karyotyping identifies thymidylate synthase amplification as a mechanism of resistance to 5-fluorouracil in metastatic colorectal cancer patients. / Wang, Tian Li; Diaz, Luis A.; Romans, Katharine; Bardelli, Alberto; Saha, Saurabh; Galizia, Gennaro; Choti, Michael; Donehower, Ross; Parmigiani, Giovanni; Shih, Ie Ming; Iacobuzio-Donahue, Christine; Kinzler, Kenneth W.; Vogelstein, Bert; Lengauer, Christoph; Velculescu, Victor E.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 101, No. 9, 02.03.2004, p. 3089-3094.

Research output: Contribution to journalArticle

Wang, TL, Diaz, LA, Romans, K, Bardelli, A, Saha, S, Galizia, G, Choti, M, Donehower, R, Parmigiani, G, Shih, IM, Iacobuzio-Donahue, C, Kinzler, KW, Vogelstein, B, Lengauer, C & Velculescu, VE 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, vol. 101, no. 9, pp. 3089-3094. https://doi.org/10.1073/pnas.0308716101
Wang, Tian Li ; Diaz, Luis A. ; Romans, Katharine ; Bardelli, Alberto ; Saha, Saurabh ; Galizia, Gennaro ; Choti, Michael ; Donehower, Ross ; Parmigiani, Giovanni ; Shih, Ie Ming ; Iacobuzio-Donahue, Christine ; Kinzler, Kenneth W. ; Vogelstein, Bert ; Lengauer, Christoph ; Velculescu, Victor E. / Digital karyotyping identifies thymidylate synthase amplification as a mechanism of resistance to 5-fluorouracil in metastatic colorectal cancer patients. In: Proceedings of the National Academy of Sciences of the United States of America. 2004 ; Vol. 101, No. 9. pp. 3089-3094.
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AU - Galizia, Gennaro

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AU - Donehower, Ross

AU - Parmigiani, Giovanni

AU - Shih, Ie Ming

AU - Iacobuzio-Donahue, Christine

AU - Kinzler, Kenneth W.

AU - Vogelstein, Bert

AU - Lengauer, Christoph

AU - Velculescu, Victor E.

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AB - 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 <0.01). These data suggest that genetic amplification of TYMS is a major mechanism of 5-FU resistance in vivo and have important implications for the management of colorectal cancer patients with recurrent disease.

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