Genome-wide screening of loci associated with drug resistance to 5-fluorouracil-based drugs

Akio Ooyama, Yoshihiro Okayama, Teiji Takechi, Yoshikazu Sugimoto, Toshinori Oka, Masakazu Fukushima

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Resistance to chemotherapeutic agents represents the chief cause of mortality in cancer patients with advanced disease. Chromosomal aberration and altered gene expression are the main genetic mechanisms of tumor chemoresistance. In this study, we have established an algorithm to calculate DNA copy number using the Affymetrix 10K array, and performed a genome-wide correlation analysis between DNA copy number and antitumor activity against 5-fluorouracil (5-FU)-based drugs (S-1, tegafur + uracil [UFT], 5′-DFUR and capecitabine) to screen for loci influencing drug resistance using 27 human cancer xenografts. A correlation analysis confirmed that the single nuceotide polymorphism (SNP) showing significant associations with drug sensitivity were concentrated in some cytogenetic regions (18p, 17p13.2, 17p12, 11q14.1, 11q11 and 11p11.12), and we identified some genes that have been indicated their relations to drug sensitivity. Among these regions, 18p11.32 at the location of the thymidylate synthase gene (TYMS) was strongly associated with resistance to 5-FU-based drugs. A change in copy number of the TYMS gene was reflected in the TYMS expression level, and showed a significant negative correlation with sensitivity against 5-FU-based drugs. These results suggest that amplification of the TYMS gene is associated with innate resistance, supporting the possibility that TYMS copy number might be a predictive marker of drug sensitivity to fluoropyrimidines. Further study is necessary to clarify the functional roles of other genes coded in significant cytogenetic regions. These promising data suggest that a comprehensive DNA copy number analysis might aid in the quest for optimal markers of drug response.

Original languageEnglish
Pages (from-to)577-583
Number of pages7
JournalCancer Science
Volume98
Issue number4
DOIs
Publication statusPublished - 2007 Apr
Externally publishedYes

Fingerprint

Drug Resistance
Fluorouracil
Thymidylate Synthase
Genome
Pharmaceutical Preparations
Genes
Cytogenetics
DNA
Tegafur
Gene Expression
Neoplasms
Gene Dosage
Uracil
Heterografts
Chromosome Aberrations
Mortality

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Genome-wide screening of loci associated with drug resistance to 5-fluorouracil-based drugs. / Ooyama, Akio; Okayama, Yoshihiro; Takechi, Teiji; Sugimoto, Yoshikazu; Oka, Toshinori; Fukushima, Masakazu.

In: Cancer Science, Vol. 98, No. 4, 04.2007, p. 577-583.

Research output: Contribution to journalArticle

Ooyama, Akio ; Okayama, Yoshihiro ; Takechi, Teiji ; Sugimoto, Yoshikazu ; Oka, Toshinori ; Fukushima, Masakazu. / Genome-wide screening of loci associated with drug resistance to 5-fluorouracil-based drugs. In: Cancer Science. 2007 ; Vol. 98, No. 4. pp. 577-583.
@article{c0870a65636d4bf58ccca5aad466a814,
title = "Genome-wide screening of loci associated with drug resistance to 5-fluorouracil-based drugs",
abstract = "Resistance to chemotherapeutic agents represents the chief cause of mortality in cancer patients with advanced disease. Chromosomal aberration and altered gene expression are the main genetic mechanisms of tumor chemoresistance. In this study, we have established an algorithm to calculate DNA copy number using the Affymetrix 10K array, and performed a genome-wide correlation analysis between DNA copy number and antitumor activity against 5-fluorouracil (5-FU)-based drugs (S-1, tegafur + uracil [UFT], 5′-DFUR and capecitabine) to screen for loci influencing drug resistance using 27 human cancer xenografts. A correlation analysis confirmed that the single nuceotide polymorphism (SNP) showing significant associations with drug sensitivity were concentrated in some cytogenetic regions (18p, 17p13.2, 17p12, 11q14.1, 11q11 and 11p11.12), and we identified some genes that have been indicated their relations to drug sensitivity. Among these regions, 18p11.32 at the location of the thymidylate synthase gene (TYMS) was strongly associated with resistance to 5-FU-based drugs. A change in copy number of the TYMS gene was reflected in the TYMS expression level, and showed a significant negative correlation with sensitivity against 5-FU-based drugs. These results suggest that amplification of the TYMS gene is associated with innate resistance, supporting the possibility that TYMS copy number might be a predictive marker of drug sensitivity to fluoropyrimidines. Further study is necessary to clarify the functional roles of other genes coded in significant cytogenetic regions. These promising data suggest that a comprehensive DNA copy number analysis might aid in the quest for optimal markers of drug response.",
author = "Akio Ooyama and Yoshihiro Okayama and Teiji Takechi and Yoshikazu Sugimoto and Toshinori Oka and Masakazu Fukushima",
year = "2007",
month = "4",
doi = "10.1111/j.1349-7006.2007.00424.x",
language = "English",
volume = "98",
pages = "577--583",
journal = "Cancer Science",
issn = "1347-9032",
publisher = "Wiley-Blackwell",
number = "4",

}

TY - JOUR

T1 - Genome-wide screening of loci associated with drug resistance to 5-fluorouracil-based drugs

AU - Ooyama, Akio

AU - Okayama, Yoshihiro

AU - Takechi, Teiji

AU - Sugimoto, Yoshikazu

AU - Oka, Toshinori

AU - Fukushima, Masakazu

PY - 2007/4

Y1 - 2007/4

N2 - Resistance to chemotherapeutic agents represents the chief cause of mortality in cancer patients with advanced disease. Chromosomal aberration and altered gene expression are the main genetic mechanisms of tumor chemoresistance. In this study, we have established an algorithm to calculate DNA copy number using the Affymetrix 10K array, and performed a genome-wide correlation analysis between DNA copy number and antitumor activity against 5-fluorouracil (5-FU)-based drugs (S-1, tegafur + uracil [UFT], 5′-DFUR and capecitabine) to screen for loci influencing drug resistance using 27 human cancer xenografts. A correlation analysis confirmed that the single nuceotide polymorphism (SNP) showing significant associations with drug sensitivity were concentrated in some cytogenetic regions (18p, 17p13.2, 17p12, 11q14.1, 11q11 and 11p11.12), and we identified some genes that have been indicated their relations to drug sensitivity. Among these regions, 18p11.32 at the location of the thymidylate synthase gene (TYMS) was strongly associated with resistance to 5-FU-based drugs. A change in copy number of the TYMS gene was reflected in the TYMS expression level, and showed a significant negative correlation with sensitivity against 5-FU-based drugs. These results suggest that amplification of the TYMS gene is associated with innate resistance, supporting the possibility that TYMS copy number might be a predictive marker of drug sensitivity to fluoropyrimidines. Further study is necessary to clarify the functional roles of other genes coded in significant cytogenetic regions. These promising data suggest that a comprehensive DNA copy number analysis might aid in the quest for optimal markers of drug response.

AB - Resistance to chemotherapeutic agents represents the chief cause of mortality in cancer patients with advanced disease. Chromosomal aberration and altered gene expression are the main genetic mechanisms of tumor chemoresistance. In this study, we have established an algorithm to calculate DNA copy number using the Affymetrix 10K array, and performed a genome-wide correlation analysis between DNA copy number and antitumor activity against 5-fluorouracil (5-FU)-based drugs (S-1, tegafur + uracil [UFT], 5′-DFUR and capecitabine) to screen for loci influencing drug resistance using 27 human cancer xenografts. A correlation analysis confirmed that the single nuceotide polymorphism (SNP) showing significant associations with drug sensitivity were concentrated in some cytogenetic regions (18p, 17p13.2, 17p12, 11q14.1, 11q11 and 11p11.12), and we identified some genes that have been indicated their relations to drug sensitivity. Among these regions, 18p11.32 at the location of the thymidylate synthase gene (TYMS) was strongly associated with resistance to 5-FU-based drugs. A change in copy number of the TYMS gene was reflected in the TYMS expression level, and showed a significant negative correlation with sensitivity against 5-FU-based drugs. These results suggest that amplification of the TYMS gene is associated with innate resistance, supporting the possibility that TYMS copy number might be a predictive marker of drug sensitivity to fluoropyrimidines. Further study is necessary to clarify the functional roles of other genes coded in significant cytogenetic regions. These promising data suggest that a comprehensive DNA copy number analysis might aid in the quest for optimal markers of drug response.

UR - http://www.scopus.com/inward/record.url?scp=34147190058&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34147190058&partnerID=8YFLogxK

U2 - 10.1111/j.1349-7006.2007.00424.x

DO - 10.1111/j.1349-7006.2007.00424.x

M3 - Article

VL - 98

SP - 577

EP - 583

JO - Cancer Science

JF - Cancer Science

SN - 1347-9032

IS - 4

ER -