We presented retrospective analysis of up to five polymorphisms in TS, MTHFR and ERCC1 genes as molecular predictive markers for homogeneous Caucasian, non-squamous NSCLC patients treated with pemetrexed and platinum front-line chemotherapy.
The following polymorphisms in DNA isolated from 115 patients were analyzed: various number of 28-bp tandem repeats in 5′-UTR region of TS gene, single nucleotide polymorphism (SNP) within the second tandem repeat of TS gene (G>C); 6-bp deletion in 3′-UTR region of the TS (1494del6); 677C>T SNP in MTHFR; 19007C>T SNP in ERCC1. Molecular examinations’ results were correlated with disease control rate, progression-free survival (PFS) and overall survival.
Polymorphic tandem repeat sequence (2R, 3R) in the enhancer region of TS gene and G>C SNP within the second repeat of 3R allele seem to be important for the effectiveness of platinum and pemetrexed in first-line chemotherapy. The insignificant shortening of PFS in 3R/3R homozygotes as compared to 2R/2R and 2R/3R genotypes were observed, while it was significantly shorter in patients carrying synchronous 3R allele and G nucleotide. The combined analysis of TS VNTR and MTHFR 677C>T SNP revealed shortening of PFS in synchronous carriers of 3R allele in TS and two C alleles in MTHFR. The strongest factors increased the risk of progression were poor PS, weight loss, anemia and synchronous presence of 3R allele and G nucleotide in the second repeat of 3R allele in TS. Moreover, lack of application of second-line chemotherapy, weight loss and poor performance status and above-mentioned genotype of TS gene increased risk of early mortality.
The examined polymorphisms should be accounted as molecular predictor factors for pemetrexed- and platinum-based front-line chemotherapy in non-squamous NSCLC patients.
Bukhari AA, Goudar RK (2013) Thymidylate synthase as predictive biomarker for pemetrexed response in NSCLC. Lung Cancer Inter 436409:1–7
Kawakami K, Watanabe G (2003) Identification and functional analysis of single nucleotide polymorphism in the tandem repeat sequence of thymidylate synthase gene. Cancer Res 63:6004–6007 PubMed
Kumar K, Vamsy M, Jamil K (2010) Thymidylate synthase gene polymorphisms effecting 5-FU response in breast cancer patients. Cancer Biomark 6(2):83–93 PubMed
Mandola MV, Stoehlmacher J, Muller-Weeks S et al (2003) A novel single nucleotide polymorphism within the 5′ tandem repeat polymorphism of the thymidylate synthase gene abolishes USF-1 binding and alters transcriptional activity. Cancer Res 63(11):2898–2904 PubMed
Mlak R, Krawczyk P, Ramlau R et al (2013) Predictive value of ERCC1 and RRM1 gene single-nucleotide polymorphisms for first-line platinum- and gemcitabine-based chemotherapy in non-small cell lung cancer patients. Oncol Rep 30(5):2385–2398 PubMed
Scagliotti G, Brodowicz T, Shepherd FA et al (2011) Treatment-by-histology interaction analyses in three phase III trials show superiority of pemetrexed in nonsquamous non-small cell lung cancer. J Thorac Oncol 6:64–70 PubMed
Sohn KJ, Croxford R, Yates Z, Lucock M, Kim YI (2013) Effect of the methylenetetrahydrofolate reductase C677T polymorphism on chemosensitivity of colon and breast cancer cells to 5-fluorouracil and methotrexate. J Natl Cancer Inst 96(2):134–144 CrossRef
Stoehlmacher J, Goekkurt E, Hoeffken G et al (2009) Thymidylate synthase polymorphisms and immunohistochemistry in non-small cell lung cancer. J Clin Oncol 27(suppl):11101
Wang X, Wang Y, Wang Y, Cheng J, Wang Y, Ha M (2013) Association of thymidylate synthase gene 3′-untranslated region polymorphism with sensitivity of non-small cell lung cancer to pemetrexed treatment: TS gene polymorphism and pemetrexed sensitivity in NSCLC. J Biomed Sci 25(20):5 CrossRef
Wang L, Wang R, Pan Y, Sun Y, Zhang J, Chen H (2014) The pemetrexed-containing treatments in the non-small cell lung cancer, is −/low thymidylate synthase expression better than +/high thymidylate synthase expression: a meta-analysis. BMC Cancer 19(14):205 CrossRef
- Polymorphisms in TS, MTHFR and ERCC1 genes as predictive markers in first-line platinum and pemetrexed therapy in NSCLC patients
Dariusz M. Kowalski
- Springer Berlin Heidelberg
Neu im Fachgebiet Onkologie
Mail Icon II