TY - JOUR
T1 - Digital karyotyping identifies thymidylate synthase amplification as a mechanism of resistance to 5-fluorouracil in metastatic colorectal cancer patients
AU - Wang, Tian Li
AU - Diaz, Luis A.
AU - Romans, Katharine
AU - Bardelli, Alberto
AU - Saha, Saurabh
AU - Galizia, Gennaro
AU - Choti, Michael
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.
PY - 2004/3/2
Y1 - 2004/3/2
N2 - 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.
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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U2 - 10.1073/pnas.0308716101
DO - 10.1073/pnas.0308716101
M3 - Article
C2 - 14970324
AN - SCOPUS:12144290775
SN - 0027-8424
VL - 101
SP - 3089
EP - 3094
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 9
ER -