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Thymidylate synthase polymorphisms are associated to therapeutic outcome of advanced non-small cell lung cancer patients treated with platinum-based chemotherapy

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Abstract

Thymidylate synthase (TYMS) has three polymorphisms that may modulate thymidylate synthase (TS) expression levels: (1) 28 base pairs (bp) variable number tandem repeat (VNTR) (rs34743033); (2) single nucleotide polymorphism (SNP) C>G at the twelfth nucleotide of the second repeat of 3R allele (rs2853542); and (3) 6 bp sequence deletion (1494del6, rs34489327). This study was conducted to evaluate the influence of TYMS polymorphisms on the survival of Portuguese patients with advanced non-small cell lung cancer (NSCLC) undergoing platinum-based chemotherapy. Our results showed no statistically significant differences between VNTR genotypes; although, considering the SNP C>G, homozygotes 3RG presented a better prognostic at 36 months (p = 0.004) and overall survival (p = 0.003) when compared to 2R3RG patients. Patients with “median/high expression genotypes” demonstrated a better survival at 12 months (p = 0.041) when compared to “low expression genotypes”. Furthermore, 6 bp− carriers (p = 0.006) showed a better survival at 12 months when compared to 6 bp+ homozygotes patients. When analyzing TYMS haplotypes, better survival at 12 months was observed for patients carrying haplotypes with the 6 bp− allele (2R6 bp−; p = 0.026 and 3RG6 bp−; p = 0.045). This is the first report that evaluates the three major TYMS polymorphisms in the therapeutic outcome of NSCLC in Portugal. According to our results, the TYMS polymorphisms may be useful tools to predict which advanced NSCLC patients could benefit more from platinum-based chemotherapy regimens.

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Acknowledgments

The authors wish to acknowledge the Ministry of Health of Portugal (CFICS-Project 31/2007) and Astrazeneca Foundation for the financial support; Liga Portuguesa Contra o Cancro—Centro Regional do Norte (Portuguese League Against Cancer) for the support to the lab; and to Fundação para a Ciência e Tecnologia (FCT) for the Doctoral Grant (SFRH/BD/64441/2009) for Aurea Lima. Authors would also like to acknowledge Hugo Sousa (Ph.D.) for his critics in the final version of the manuscript.

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Authors and Affiliations

  1. IINFACTS/CESPU, Institute of Research and Advanced Training in Health Sciences and Technologies, Department of Pharmaceutical Sciences, Higher Institute of Health Sciences (ISCS-N), Rua Central de Gandra 1317, 4585-116, Gandra PRD, Portugal

    Aurea Lima & Vítor Seabra

  2. Molecular Oncology Group CI, Portuguese Institute of Oncology of Porto (IPO-Porto), Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal

    Aurea Lima, Ana Coelho, António Araújo & Rui Medeiros

  3. Abel Salazar Institute for the Biomedical Sciences (ICBAS), University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313, Porto, Portugal

    Aurea Lima & Rui Medeiros

  4. Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Rua Dr. Roberto Frias, 4200-465, Porto, Portugal

    Sandra Martins

  5. Faculty of Medicine of University of Porto (FMUP), Al. Prof. Hernâni Monteiro, 4200-319, Porto, Portugal

    Ana Coelho

  6. Medical Oncology Department, Portuguese Institute of Oncology of Porto (IPO-Porto), Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal

    António Araújo

  7. Research Department, Portuguese League Against Cancer (LPCC-NRNorte), Estrada Interior da Circunvalação, 6657, 4200-177, Porto, Portugal

    Rui Medeiros

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  1. Aurea Lima
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Correspondence to Aurea Lima.

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Lima, A., Seabra, V., Martins, S. et al. Thymidylate synthase polymorphisms are associated to therapeutic outcome of advanced non-small cell lung cancer patients treated with platinum-based chemotherapy. Mol Biol Rep 41, 3349–3357 (2014). https://doi.org/10.1007/s11033-014-3197-3

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