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Published on: September 20, 2016
Genomic copy number changes affecting the thymidylate synthase (TYMS) gene in cancer: a model for patient
Jonathan R Brody1, Tomas Hucl, Eike Gallmeier
1The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Abstract:
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.
Insights
Thymidylate synthase (TS) copy number changes, including loss of heterozygosity and polysomy, significantly impact 5-fluorouracil (5FU) chemotherapy sensitivity in gastrointestinal cancers, suggesting TS copy number is a key factor in treatment response.
Area of Science:
- Oncology
- Cancer Genetics
- Pharmacogenomics
Background:
- Thymidylate synthase (TS) is a critical target for 5-fluorouracil (5FU) chemotherapy.
- Current 5FU treatment guidance often overlooks TS gene copy number variations.
- Polymorphisms in the TS 5'-untranslated region are being investigated for predicting 5FU efficacy.
Purpose of the Study:
- To investigate the role of thymidylate synthase (TS) gene copy number alterations in gastrointestinal cancers.
- To determine how TS copy number variations affect sensitivity to 5-fluorouracil (5FU) and related drugs.
- To establish a model for predicting 5FU responsiveness based on TS genetic status.
Main Methods:
- Surveyed TS tandem repeat sequences in gastrointestinal cancer samples to identify copy number changes.
- Utilized genetic engineering in a colorectal cancer cell line to create artificial loss of heterozygosity (LOH) at the TS locus.
- Assessed TS protein expression and drug sensitivity (5FU, 5-fluoro-2'-deoxyuridine) in engineered cell lines with varying TS gene copies.
Main Results:
- Observed copy number changes, including LOH and allelic imbalance due to polysomy, at the TS locus in gastrointestinal cancers.
- Engineered TS(+/-) cells exhibited reduced TS protein expression and hypersensitivity to 5FU and 5-fluoro-2'-deoxyuridine.
- Restoration of TS expression in engineered cells normalized drug sensitivity, confirming the link to TS copy number.
Conclusions:
- Tumor 5FU sensitivity is influenced by aneuploidy-driven TS copy number changes, such as LOH and polysomy.
- TS gene copy number is a potentially dominant factor determining a patient's response to 5FU-based therapy.
- Clinical assessment of TS copy number may improve patient stratification for 5FU treatment.
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