Thymidylate synthase polymorphisms are associated to therapeutic outcome of advanced non-small cell lung cancer patients treated with platinum-based chemotherapy Aurea Lima • Vı ´tor Seabra • Sandra Martins • Ana Coelho • Anto ´nio Arau ´jo • Rui Medeiros Received: 9 January 2013 / Accepted: 24 January 2014 / Published online: 20 February 2014 Ó Springer Science+Business Media Dordrecht 2014 Abstract Thymidylate synthase (TYMS) has three poly- morphisms 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 polymor- phisms on the survival of Portuguese patients with advanced non-small cell lung cancer (NSCLC) undergoing platinum-based chemotherapy. Our results showed no sta- tistically 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 geno- types’’ 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 hap- lotypes, 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 poly- morphisms in the therapeutic outcome of NSCLC in Por- tugal. According to our results, the TYMS polymorphisms may be useful tools to predict which advanced NSCLC patients could benefit more from platinum-based chemo- therapy regimens. Keywords NSCLC Á Platinum-based chemotherapy Á Polymorphisms Á Therapeutic outcome Á Thymidylate synthase A. Lima (&) Á V. Seabra 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 e-mail: aurea.lima@iscsn.cespu.pt; aurealima1010@hotmail.com A. Lima Á A. Coelho Á A. Arau ´jo Á R. Medeiros Molecular Oncology Group CI, Portuguese Institute of Oncology of Porto (IPO-Porto), Rua Dr. Anto ´nio Bernardino de Almeida, 4200-072 Porto, Portugal A. Lima Á R. Medeiros Abel Salazar Institute for the Biomedical Sciences (ICBAS), University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal S. Martins Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Rua Dr. Roberto Frias, 4200-465 Porto, Portugal A. Coelho Faculty of Medicine of University of Porto (FMUP), Al. Prof. Herna ˆni Monteiro, 4200-319 Porto, Portugal A. Arau ´jo Medical Oncology Department, Portuguese Institute of Oncology of Porto (IPO-Porto), Rua Dr. Anto ´nio Bernardino de Almeida, 4200-072 Porto, Portugal R. Medeiros Research Department, Portuguese League Against Cancer (LPCC-NRNorte), Estrada Interior da Circunvalac ¸a ˜o, 6657, 4200-177 Porto, Portugal 123 Mol Biol Rep (2014) 41:3349–3357 DOI 10.1007/s11033-014-3197-3 WARNING This document has been supplied under a CLA Licence. It is protected by copyright and it may not (even for internal purposes) be further copied, stored or on-copied electronically without permission, save as may be permitted by law. The recipient may print out a single copy of any document received electronically.