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The Werner’s syndrome 4330T>C (Cys1367Arg) gene variant does not affect the in vitro cytotoxicity of topoisomerase inhibitors and platinum compounds

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Abstract

Purpose

Werner’s syndrome (WS) is a recessive disorder of premature onset of processes associated with aging. Defective DNA repair has been reported after exposure of cells isolated from WS patients to DNA-damaging agents. The germline 4330T>C (Cys1367Arg) variant in the WS gene (WRN) has been associated with protection from age-related diseases, suggesting it has a functional role. We studied whether the 4330T>C variant confers altered drug sensitivity in vitro.

Methods

4330T>C was genotyped in 372 human lymphoblastoid cell lines (LCLs) from unrelated healthy Caucasian individuals using a TaqMan-based method. The study was powered to detect the effect of the 4330T>C genotypes after exposure to camptothecin (based upon preliminary data). The effect of the 4330T>C variant on the cytotoxicity of etoposide, carboplatin, cisplatin and daunorubicin was also tested. WRN expression in 57 LCLs was measured by microarray.

Results

No significant difference between the IC50 of the cells was observed among genotypes (P = 0.46) after exposure to camptothecin. No association was also observed for etoposide, carboplatin, cisplatin, and daunorubicin (ANOVA, P > 0.05). WRN expression also did not vary across genotypes (ANOVA, P = 0.37).

Conclusion

These results suggest that this nonsynonymous variant has relatively normal function at the cellular level.

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Abbreviations

WS:

Werner’s syndrome

WRN:

Werner’s syndrome gene

LCLs:

Lymphoblastoid cell lines

4NQO:

4-Nitro-quinoline-1-oxide

SNPs:

Single nucleotide polymorphisms

EBV:

Epstein–Barr virus

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Acknowledgments

This work was supported by the Pharmacogenetics of Anticancer Agents Research (PAAR) Group (http://pharmacogenetics.org) (NIH/NIGMS grant U01GM61393). Data has been deposited into PharmGKB (supported by NIH/NIGMS U01GM61374, hhtp://pharmgkb.org/) under submission numbers PS207132, PS207134, PS206923, PS206922, PS206925 and PS207015 for WRN genotype and sensitivity to camptothecin, cisplatin, etoposide, daunorubicin and carboplatin, respectively. The authors wish to thank the PAAR Lymphoblastoid Cell Core at the University of Chicago (directed at the time of this study by Dr. Amittha Wickrema) for maintaining the lymphoblastoid cell lines used in this study.

Author information

Authors and Affiliations

  1. Department of Medicine, The University of Chicago, 5841 South Maryland Avenue, MC 2115, Chicago, IL, 60637, USA

    Federico Innocenti, Snezana Mirkov, Jacqueline Ramírez, Wanqing Liu, Wasim K. Bleibel, Sunita J. Shukla, M. Eileen Dolan & Mark J. Ratain

  2. Department of Pediatrics, The University of Chicago, Chicago, IL, USA

    Ramamoorthy Nagasubramanian

  3. Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, Chicago, IL, USA

    Federico Innocenti, M. Eileen Dolan & Mark J. Ratain

  4. Cancer Research Center, The University of Chicago, Chicago, IL, USA

    Federico Innocenti, M. Eileen Dolan & Mark J. Ratain

  5. Department of Psychiatry, The University of Illinois at Chicago, Chicago, IL, USA

    Kathleen Hennessy & Edwin Cook Jr

  6. MD Anderson Cancer Center, The University of Texas, Houston, TX, USA

    Gary L. Rosner

Authors
  1. Federico Innocenti
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  2. Snezana Mirkov
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  5. Wanqing Liu
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  11. M. Eileen Dolan
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  12. Mark J. Ratain
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Correspondence to Federico Innocenti.

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Innocenti, F., Mirkov, S., Nagasubramanian, R. et al. The Werner’s syndrome 4330T>C (Cys1367Arg) gene variant does not affect the in vitro cytotoxicity of topoisomerase inhibitors and platinum compounds. Cancer Chemother Pharmacol 63, 881–887 (2009). https://doi.org/10.1007/s00280-008-0793-8

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  • DOI: https://doi.org/10.1007/s00280-008-0793-8

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