Genomic copy number changes affecting the thymidylate synthase (TYMS) gene in cancer: a model for patient classification to aid fluoropyrimidine therapy.

Genomic copy number changes affecting the thymidylate synthase (TYMS) gene in cancer: a model for patient classification to aid fluoropyrimidine therapy. Research Abstract Details 

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Genomic copy number changes affecting the thymidylate synthase (TYMS) gene in cancer: a model for patient classification to aid fluoropyrimidine therapy. Abstract Text:

Jonathan R Brody,Tomas Hucl,Eike Gallmeier,Jordan M Winter,Scott E Kern,Kathleen M Murphy,

Thymidylate synthase (TS) is an important target for 5-fluorouracil (5FU)-based therapy. The TS polymorphic 5'-untranslated region tandem repeat sequence is under investigation to guide 5FU treatment, yet current protocols omit consideration of copy number changes at the TS locus. We surveyed the TS tandem repeat sequence and found copy number changes in gastrointestinal cancers. Ten of 12 informative cases had loss of heterozygosity (LOH), whereas two others and an additional cell line had a novel TS genotype, allelic imbalance at the TS locus due to polysomy. Experimentally, we studied a diploid colorectal cancer line heterozygous at TS to mimic three common TS genotypes of cancers. Using genetic engineering, we deleted the short tandem repeat (two repeats) allele and retained the long (three repeats) allele to produce artificial LOH at the TS gene; the TS(+/-) line had a reduced TS protein expression and was hypersensitive to 5FU and 5-fluoro-2'-deoxyuridine in vitro as compared with syngeneic control lines. We linked this sensitivity directly to the reduced TS expression by introducing exogenous TS cDNA expression into the TS(+/-) line (i.e., increased TS copies). Our model predicts that the 5FU sensitivity of a tumor is modified by aneuploidy producing copy number changes of TS alleles by one or more of the following: LOH, amplification, and, as presented here, copy number changes due to polysomy. The data suggest that TS copy number in a patient's tumor may be a dominating variable affecting 5FU responsiveness.

Genomic copy number changes affecting the thymidylate synthase (TYMS) gene in cancer: a model for patient classification to aid fluoropyrimidine therapy. Publishing Authors By Initials

JR Brody,T Hucl,E Gallmeier,JM Winter,SE Kern,KM Murphy,

For similar surgical procedures, operative: transplantation: transplantation, heterologous research abstracts see: surgical procedures, operative: transplantation: transplantation, heterologous research

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Genomic copy number changes affecting the thymidylate synthase (TYMS) gene in cancer: a model for patient classification to aid fluoropyrimidine therapy. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: Cancer research

VOLUME: 66

Page Numbers: 9369-73

Journal Abbreviation: Cancer Res.

ISSN: 1538-7445

DAY: 1

MONTH: Oct

YEAR: 2006

Genomic copy number changes affecting the thymidylate synthase (TYMS) gene in cancer: a model for patient classification to aid fluoropyrimidine therapy. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 2984705

Genomic copy number changes affecting the thymidylate synthase (TYMS) gene in cancer: a model for patient classification to aid fluoropyrimidine therapy. Keywords Mesh Terms:

KEYWORDS: Transplantation, Heterologous

MESH TERMS: physiology

Chemical & Substance for Abstract: Genomic copy number changes affecting the thymidylate synthase (TYMS) gene in cancer: a model for patient classification to aid fluoropyrimidine therapy. Information

Substance Name: Thymidylate Synthase

Registry Number: EC 2.1.1.45

Grant and Affiliation Information for Genomic copy number changes affecting the thymidylate synthase (TYMS) gene in cancer: a model for patient classification to aid fluoropyrimidine therapy.

AFFILIATION: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Country: United States

AGENCY: United States NIDDK

GRANT: T32-DK007713

ACRONYM: DK

MEDLINETA: Cancer Res

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