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Pharmacogenetic variants associated with outcome in patients with advanced gastric cancer treated with fluoropyrimidine and platinum-based triplet combinations: a pooled analysis of three prospective studies

The Pharmacogenomics Journal volume 17, pages 441–451 (2017)Cite this article

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Abstract

The main treatment for advanced gastric cancer is fluoropyrimidine and platinum-based chemotherapy. We investigated the clinical validitiy of 19 candidate pharmacogenetic variants in ENOSF1 (enolase superfamily member 1), TYMS, CDA, MTHFR, TYMP, DPYD, ERCC1, ERCC2, GSTP1, GSTT1, GSTM1, CYP3A4 and CYP3A5 in relation to overall survival (OS), progression-free survival, objective response rate (ORR) and toxicity in 185 patients receiving triplet chemotherapy. The formal significance threshold was P<0.0026. TYMS VNTR (variable number of 28-bp tandem repeats) 3 R/3 R genotype was formally associated with inferior ORR (odds ratio (OR) 0.3, P=0.0025), whereas ENOSF1 rs2612091 G/G was nominally associated with OS after adjustment for TYMS 3 R/3 R (hazard ratio (HR) 1.5, P=0.041). In a subgroup analysis of patients with locally advanced disease (n=33), ENOSF1 rs2612091 was strongly associated with OS (HR 6.5, P=0.001). CYP3A4*22/CYP3A5*3 genotype was nominally associated with grade 3/4 toxicity in patients receiving docetaxel-containing chemotherapy (P=0.0175). This is the first study suggesting that ENOSF1 rs2612091 is prognostic or predictive of OS in gastric cancer. This finding requires prospective validation.

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References

  1. World Health Organization (WHO). Available at: http://www.who.int/; last accessed on January 2, 2015.

  2. Wagner AD, Unverzagt S, Grothe W, Kleber G, Grothey A, Haerting J et al. Chemotherapy for advanced gastric cancer. Cochrane database Syst Rev 2010; 3: CD004064.

    Google Scholar 

  3. Wang J, Xu R, Li J, Bai Y, Liu T, Jiao S et al. Randomized multicenter phase III study of a modified docetaxel and cisplatin plus fluorouracil regimen compared with cisplatin and fluorouracil as first-line therapy for advanced or locally recurrent gastric cancer. Gastric Cancer 2016; 19: 234–244.

    Article  CAS  PubMed  Google Scholar 

  4. Van Cutsem E, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C et al. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol 2006; 24: 4991–4997.

    Article  CAS  PubMed  Google Scholar 

  5. Waddell T, Chau I, Cunningham D, Gonzalez D, Okines AFC, Frances A et al. Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial. Lancet Oncol 2013; 14: 481–489.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F et al. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med 2008; 358: 36–46.

    Article  CAS  PubMed  Google Scholar 

  7. Goekkurt E, Al-Batran S-E, Hartmann JT, Mogck U, Schuch G, Kramer M et al. Pharmacogenetic analyses of a phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil and leucovorin plus either oxaliplatin or cisplatin: a study of the arbeitsgemeinschaft internistische onkologie. J Clin Oncol 2009; 27: 2863–2873.

    Article  CAS  PubMed  Google Scholar 

  8. Ruzzo A, Graziano F, Kawakami K, Watanabe G, Santini D, Catalano V et al. Pharmacogenetic profiling and clinical outcome of patients with advanced gastric cancer treated with palliative chemotherapy. J Clin Oncol 2006; 24: 1883–1891.

    Article  CAS  PubMed  Google Scholar 

  9. Lu J-W, Gao C-M, Wu J-Z, Cao H-X, Tajima K, Feng J-F . Polymorphism in the 3′-untranslated region of the thymidylate synthase gene and sensitivity of stomach cancer to fluoropyrimidine-based chemotherapy. J Hum Genet 2006; 51: 155–160.

    Article  CAS  PubMed  Google Scholar 

  10. Keam B, Im S-A, Han S-W, Ham HS, Kim MA, Oh D-Y et al. Modified FOLFOX-6 chemotherapy in advanced gastric cancer: results of phase II study and comprehensive analysis of polymorphisms as a predictive and prognostic marker. BMC Cancer 2008; 8: 148.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Cui YH, Liu TS, Zhuang RY, Gao HJ, Li H . Polymorphism of thymidylate synthase gene and chemosensitivity of 5-fluorouracil regimen in metastatic gastrointestinal cancer. J Dig Dis 2009; 10: 118–123.

    Article  CAS  PubMed  Google Scholar 

  12. Han S-W, Oh D-Y, Im S-A, Park SR, Lee K-W, Song HS et al. Epidermal growth factor receptor intron 1 CA dinucleotide repeat polymorphism and survival of advanced gastric cancer patients treated with cetuximab plus modified FOLFOX6. Cancer Sci 2010; 101: 793–799.

    Article  CAS  PubMed  Google Scholar 

  13. Shitara K, Muro K, Ito S, Sawaki A, Tajika M, Kawai H et al. Folate intake along with genetic polymorphisms in methylenetetrahydrofolate reductase and thymidylate synthase in patients with advanced gastric cancer. Cancer Epidemiol Biomarkers Prev 2010; 19: 1311–1319.

    Article  CAS  PubMed  Google Scholar 

  14. Gao J, He Q, Hua D, Mao Y, Li Y, Shen L . Polymorphism of TS 3’-UTR predicts survival of Chinese advanced gastric cancer patients receiving first-line capecitabine plus paclitaxel. Clin Transl Oncol 2013; 15: 619–625.

    Article  CAS  PubMed  Google Scholar 

  15. Popat S, Matakidou A, Houlston RS . Thymidylate synthase expression and prognosis in colorectal cancer: a systematic review and meta-analysis. J Clin Oncol 2004; 22: 529–536.

    Article  CAS  PubMed  Google Scholar 

  16. Yeh K, Shun C, Lin J, Ph D, Lee W, Lee P et al. High expression of thymidylate synthase is associated with the drug resistance of gastric carcinoma to high dose 5-fluorouracil-based systemic chemotherapy. Cancer 1997; 82: 1626–1631.

    Article  Google Scholar 

  17. Boku N, Chin K, Hosokawa K, Ohtsu A, Tajiri H, Yoshida S et al. Biological markers as a predictor for response and prognosis of unresectable gastric cancer patients treated with 5-fluorouracil and cis-platinum. Clin Cancer Res 1998; 4: 1469–1474.

    CAS  PubMed  Google Scholar 

  18. Horie N, Aiba H, Oguro K, Hojo H, Takeishi K . Functional analysis and DNA polymorphism of the tandemly repeated sequences in the 5′-terminal regulatory region of the human gene for thymidylate synthase. Cell Struct Funct 1995; 20: 191–197.

    Article  CAS  PubMed  Google Scholar 

  19. Kawakami K, Salonga D, Park JM, Danenberg KD, Uetake H, Brabender J et al. Different lengths of a polymorphic repeat sequence in the thymidylate synthase gene affect translational efficiency but not its gene expression. Clin Cancer Res 2001; 7: 4096–4101.

    CAS  PubMed  Google Scholar 

  20. Mandola MV, Stoehlmacher J, Muller-Weeks S, Cesarone G, Yu MC, Lenz H et al. 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 2003; 63: 2898–2904.

    CAS  PubMed  Google Scholar 

  21. Kawakami K, Omura K, Kanehira E, Watanabe Y . Polymorphic tandem repeats in the thymidylate synthase gene is associated with its protein expression in human gastrointestinal cancers. Anticancer Res 1999; 19: 3249–3252.

    CAS  PubMed  Google Scholar 

  22. Mandola MV, Stoehlmacher J, Zhang W, Groshen S, Yu MC, Iqbal S et al. A 6 bp polymorphism in the thymidylate synthase gene causes message instability and is associated with decreased intratumoral TS mRNA levels. Pharmacogenetics 2004; 14: 319–327.

    Article  CAS  PubMed  Google Scholar 

  23. Pullarkat ST, Stoehlmacher J, Ghaderi V, Xiong YP, Ingles SA, Sherrod A et al. Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy. Pharmacogenomics J 2001; 1: 65–70.

    Article  CAS  PubMed  Google Scholar 

  24. Morganti M, Ciantelli M, Giglioni B, Putignano AL, Nobili S, Papi L et al. Relationships between promoter polymorphisms in the thymidylate synthase gene and mRNA levels in colorectal cancers. Eur J Cancer 2005; 41: 2176–2183.

    Article  CAS  PubMed  Google Scholar 

  25. Joerger M, Huitema ADR, Boot H, Cats A, Doodeman VD, Smits PHM et al. Germline TYMS genotype is highly predictive in patients with metastatic gastrointestinal malignancies receiving capecitabine-based chemotherapy. Cancer Chemother Pharmacol 2015; 75: 763–772.

    Article  CAS  PubMed  Google Scholar 

  26. Goekkurt E, Hoehn S, Wolschke C, Wittmer C, Stueber C, Hossfeld DK et al. Polymorphisms of glutathione S-transferases (GST) and thymidylate synthase (TS)—novel predictors for response and survival in gastric cancer patients. Br J Cancer 2006; 94: 281–286.

    Article  CAS  PubMed  Google Scholar 

  27. Seo B, Kwon H, Oh SY, Lee S, Kim S, Kim S et al. Comprehensive analysis of excision repaircomplementation group 1, glutathione S-transferase, thymidylate synthase and uridinediphosphate glucuronosyl transferase 1A1 polymorphisms predictive for treatment outcome inpatients with advanced gastric cancer treated with FOLFOX or FOLFIRI. Oncol Rep 2009; 22: 127–136.

    CAS  PubMed  Google Scholar 

  28. Rosmarin D, Palles C, Pagnamenta A, Kaur K, Pita G, Martin M et al. A candidate gene study of capecitabine-related toxicity in colorectal cancer identifies new toxicity variants at DPYD and a putative role for ENOSF1 rather than TYMS. Gut 2015; 64: 111–120.

    Article  CAS  PubMed  Google Scholar 

  29. Dolnick BJ . The rTS signaling pathway as a target for drug development. Clin Colorectal Cancer 2005; 5: 57–60.

    Article  CAS  PubMed  Google Scholar 

  30. Chu E, Koeller DM, Casey JL, Drake JC, Chabner BA, Elwood PC et al. Autoregulation of human thymidylate synthase messenger RNA translation by thymidylate synthase. Proc Natl Acad Sci USA 1991; 88: 8977–8981.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Rosmarin D, Palles C, Church D, Domingo E, Jones A, Johnstone E et al. Genetic markers of toxicity from capecitabine and other fluorouracil-based regimens: investigation in the QUASAR2 study, systematic review, and meta-analysis. J Clin Oncol 2014; 32: 1031–1039.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Patel JN, Fuchs CS, Owzar K, Chen Z, McLeod HL . Gastric cancer pharmacogenetics: progress or old tripe? Pharmacogenomics 2013; 14: 1053–1064.

    Article  CAS  PubMed  Google Scholar 

  33. Lunn RM, Helzlsouer KJ, Parshad R, Umbach DM, Harris EL, Sanford KK et al. XPD polymorphisms: effects on DNA repair proficiency. Carcinogenesis 2000; 21: 551–555.

    Article  CAS  PubMed  Google Scholar 

  34. Yu JJ, Lee KB, Mu C, Li Q, Abernathy T V, Bostick-Bruton F et al. Comparison of two human ovarian carcinoma cell lines (A2780/CP70 and MCAS) that are equally resistant to platinum, but differ at codon 118 of the ERCC1 gene. Int J Oncol 2000; 16: 555–560.

    CAS  PubMed  Google Scholar 

  35. Yin M, Yan J, Martinez-Balibrea E, Graziano F, Lenz H-J, Kim H-J et al. ERCC1 and ERCC2 polymorphisms predict clinical outcomes of oxaliplatin-based chemotherapies in gastric and colorectal cancer: a systemic review and meta-analysis. Clin Cancer Res 2011; 17: 1632–1640.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Reed E . Platinum-DNA adduct, nucleotide excision repair and platinum based anti-cancer chemotherapy. Cancer Treat Rev 1998; 24: 331–344.

    Article  CAS  PubMed  Google Scholar 

  37. de Graan A-JM, Elens L, Sprowl JA, Sparreboom A, Friberg LE, van der Holt B et al. CYP3A4*22 genotype and systemic exposure affect paclitaxel-induced neurotoxicity. Clin Cancer Res 2013; 19: 3316–3324.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Werk AN, Cascorbi I . Functional gene variants of CYP3A4. Clin Pharmacol Ther 2014; 96: 340–348.

    Article  CAS  PubMed  Google Scholar 

  39. Deenen MJ, Meulendijks D, Boot H, Legdeur MC, Beijnen JH, Schellens JH et al. Phase 1a/1b and pharmacogenetic study of docetaxel, oxaliplatin and capecitabine in patients with advanced cancer of the stomach or the gastroesophageal junction. Cancer Chemotherapy and Pharmacology 2015; 76: 1285–1295.

    Article  CAS  PubMed  Google Scholar 

  40. Meulendijks D, de Groot JW, Los M, Boers JE, Beerepoot LV, Polee MB et al. Bevacizumab combined with docetaxel, oxaliplatin, and capecitabine, followed by maintenance with capecitabine and bevacizumab, as first-line treatment of patients with advanced HER2-negative gastric cancer: A multicenter phase 2 study. Cancer 2016; 122: 1434–1443.

    Article  CAS  PubMed  Google Scholar 

  41. Meulendijks D, Beerepoot LV, Boot H, de Groot JW, Los M, Boers JE et al. Trastuzumab and bevacizumab combined with docetaxel, oxaliplatin and capecitabine as first-line treatment of advanced HER2-positive gastric cancer: a multicenter phase II study. Investigational New Drugs 2016; 34: 119–128.

    Article  CAS  PubMed  Google Scholar 

  42. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228–247.

    Article  CAS  PubMed  Google Scholar 

  43. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92: 205–216.

    Article  CAS  PubMed  Google Scholar 

  44. Dolnick B, Angelino N . A novel function for the rTS gene. Cancer Biol Ther 2003; 2: 364–369.

    Article  CAS  PubMed  Google Scholar 

  45. Elens L, Nieuweboer A, Clarke SJ, Charles KA, de Graan A-J, Haufroid V et al. CYP3A4 intron 6 C&gt;T SNP (CYP3A4*22) encodes lower CYP3A4 activity in cancer patients, as measured with probes midazolam and erythromycin. Pharmacogenomics 2013; 14: 137–149.

    Article  CAS  PubMed  Google Scholar 

  46. Wigginton JE, Cutler DJ, Abecasis GR . A note on exact tests of Hardy–Weinberg equilibrium. Am J Hum Genet 2005; 76: 887–893.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Barrett JC, Fry B, Maller J, Daly MJ . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–265.

    Article  CAS  PubMed  Google Scholar 

  48. Davies AR, Gossage JA, Zylstra J, Mattsson F, Lagergren J, Maisey N et al. Tumor stage after neoadjuvant chemotherapy determines survival after surgery for adenocarcinoma of the esophagus and esophagogastric junction. J Clin Oncol 2014; 32: 2983–2990.

    Article  PubMed  Google Scholar 

  49. Abramowicz A, Wojakowska A, Gdowicz-Klosok A, Polanska J, Rodziewicz P, Polanowski P et al. Identification of serum proteome signatures of locally advanced and metastatic gastric cancer: a pilot study. J Transl Med 2015; 13: 304.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Ohtsu A, Shah MA, Van Cutsem E, Rha SY, Sawaki A, Park SR et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol 2011; 29: 3968–3976.

    Article  CAS  PubMed  Google Scholar 

  51. Wöhrer SS, Raderer M, Hejna M . Palliative chemotherapy for advanced gastric cancer. Ann Oncol 2004; 15: 1585–1595.

    Article  PubMed  Google Scholar 

  52. Dolnick BJ . Cloning and characterization of a naturally occurring antisense RNA to human thymidylate synthase mRNA. Nucleic Acids Res 1993; 21: 1747–1752.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Chu J, Dolnick BJ . Natural antisense (rTS a) RNA induces site-specific cleavage of thymidylate synthase mRNA. Biochim Biophys Acta 2002; 1587: 183–193.

    Article  CAS  PubMed  Google Scholar 

  54. Dolnick BJ, Black AR . Alternate splicing of the rTS gene product and its overexpression in a 5-fluorouracil-resistant cell line. Cancer Res 1996; 56: 3207–3210.

    CAS  PubMed  Google Scholar 

  55. Grau JJ, Domingo-Domenech J, Morente V, Pera M, Garcia-Valdecasas JC, Fuster J et al. Low thymidylate synthase expression in the primary tumor predicts favorable clinical outcome in resected gastric cancer patients treated with adjuvant tegafur. Oncology 2004; 66: 226–233.

    Article  CAS  PubMed  Google Scholar 

  56. Joshi MM, Shirota Y, Danenberg KD, Conlon DH, Salonga DS, Ii JEH et al. High gene expression of TS1, GSTP1, and ERCC1 are risk factors for survival in patients treated with trimodality therapy for esophageal cancer. Clin Cancer Res 2005; 11: 2215–2221.

    Article  PubMed  Google Scholar 

  57. Hua D, Huang Z, Mao Y, Deng J . Thymidylate synthase and thymidine phosphorylase gene expression as predictive parameters for the efficacy of 5-fluorouraci-based adjuvant chemotherapy for gastric cancer. World J Gastroenterol 2007; 13: 5030–5034.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Shirota Y, Stoehlmacher J, Brabender J, Xiong YP, Uetake H, Danenberg KD et al. ERCC1 and thymidylate synthase mRNA levels predict survival for colorectal cancer patients receiving combination oxaliplatin and fluorouracil chemotherapy. J Clin Oncol 2001; 19: 4298–4304.

    Article  CAS  PubMed  Google Scholar 

  59. Paré L, Marcuello E, Altés A, del Río E, Sedano L, Salazar J et al. Pharmacogenetic prediction of clinical outcome in advanced colorectal cancer patients receiving oxaliplatin/5-fluorouracil as first-line chemotherapy. Br J Cancer 2008; 99: 1050–1055.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Rumiato E, Cavallin F, Boldrin E, Cagol M, Alfieri R, Basso D et al. ERCC1 C8092A (rs3212986) polymorphism as a predictive marker in esophageal cancer patients treated with cisplatin/5-FU-based neoadjuvant therapy. Pharmacogenet Genomics 2013; 23: 597–604.

    Article  CAS  PubMed  Google Scholar 

  61. Kim KH, Kwon H-C, Oh SY, Kim SH, Lee S, Kwon KA et al. Clinicopathologic significance of ERCC1, thymidylate synthase and glutathione S-transferase P1 expression for advanced gastric cancer patients receiving adjuvant 5-FU and cisplatin chemotherapy. Biomarkers 2011; 16: 74–82.

    Article  CAS  PubMed  Google Scholar 

  62. Ruzzo A, Graziano F, Kawakami K, Watanabe G, Santini D, Catalano V et al. Pharmacogenetic profiling and clinical outcome of patients with advanced gastric cancer treated with palliative chemotherapy. J Clin Oncol 2006; 24: 1883–1891.

    Article  CAS  PubMed  Google Scholar 

  63. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995; 10: 111–113.

    Article  CAS  PubMed  Google Scholar 

  64. Gilbert J a, Salavaggione OE, Ji Y, Pelleymounter LL, Eckloff BW, Wieben ED et al. Gemcitabine pharmacogenomics: cytidine deaminase and deoxycytidylate deaminase gene resequencing and functional genomics. Clin Cancer Res 2006; 12: 1794–1803.

    Article  CAS  PubMed  Google Scholar 

  65. Loganayagam A, Arenas Hernandez M, Corrigan A, Fairbanks L, Lewis CM, Harper P et al. Pharmacogenetic variants in the DPYD, TYMS, CDA and MTHFR genes are clinically significant predictors of fluoropyrimidine toxicity. Br J Cancer 2013; 108: 2505–2515.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Jennings BA, Loke YK, Skinner J, Keane M, Chu GS, Turner R et al. Evaluating predictive pharmacogenetic signatures of adverse events in colorectal cancer patients treated with fluoropyrimidines. PLoS ONE 2013; 8: e78053.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. van Kuilenburg ABP, Meijer J, ANPM Mul, Meinsma R, Schmid V, Dobritzsch D et al. Intragenic deletions and a deep intronic mutation affecting pre-mRNA splicing in the dihydropyrimidine dehydrogenase gene as novel mechanisms causing 5-fluorouracil toxicity. Hum Genet 2010; 128: 529–538.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Deenen MJ, Tol J, Burylo AM, Doodeman VD, de Boer A, Vincent A et al. Relationship between single nucleotide polymorphisms and haplotypes in DPYD and toxicity and efficacy of capecitabine in advanced colorectal cancer. Clin Cancer Res 2011; 17: 3455–3468.

    Article  CAS  PubMed  Google Scholar 

  69. Froehlich TK, Amstutz U, Aebi S, Joerger M, Programme PO, Hospital C . Clinical importanceof risk variants in the dihydropyrimidine dehydrogenase gene for the prediction of early-onset fluoropyrimidine toxicity. Int J Cancer 2105; 136: 730–739.

    Google Scholar 

  70. Seck K, Riemer S, Kates R, Ullrich T, Lutz V, Harbeck N et al. Analysis of the DPYD gene implicated in 5-fluorouracil catabolism in a cohort of Caucasian individuals. Clin Cancer Res 2005; 11: 5886–5892.

    Article  CAS  PubMed  Google Scholar 

  71. Offer SM, Fossum CC, Wegner NJ, Stufflesser AJ, Butterfield GL, Diasio RB et al. Comparative functional analysis of DPYD variants of potential clinical relevance to dihydropyrimidine dehydrogenase activity. Cancer Res 2014; 74: 2545–2554.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Amstutz U, Farese S, Aebi S, Largiadèr CR . Dihydropyrimidine dehydrogenase gene variation and severe 5-fluorouracil toxicity: a haplotype assessment. Pharmacogenomics 2009; 10: 931–944.

    Article  CAS  PubMed  Google Scholar 

  73. Schwab M, Zanger UM, Marx C, Schaeffeler E, Klein K, Dippon J et al. Role of genetic and nongenetic factors for fluorouracil treatment-related severe toxicity: a prospective clinical trial by the German 5-FU Toxicity Study Group. J Clin Oncol 2008; 26: 2131–2138.

    Article  CAS  PubMed  Google Scholar 

  74. Terrazzino S, Cargnin S, Del Re M, Danesi R, Canonico PL, Genazzani AA . DPYD IVS14+1G&gt;A and 2846 A&gt;T genotyping for the prediction of severe fluoropyrimidine-related toxicity: a meta-analysis. Pharmacogenomics 2013; 14: 1255–1272.

    Article  CAS  PubMed  Google Scholar 

  75. van Kuilenburg ABP, Haasjes J, Richel DJ, Zoetekouw L, Van Lenthe H, De Abreu RA et al. Clinical implications of dihydropyrimidine dehydrogenase (DPD) deficiency in patients with severe 5-fluorouracil-associated toxicity: identification of new mutations in the DPD gene. Clin Cancer Res 2000; 6: 4705–4712.

    CAS  PubMed  Google Scholar 

  76. Deenen MJ, Cats A, Beijnen JH, Schellens JHM . Part 3: Pharmacogenetic variability in phase II anticancer drug metabolism. Oncologist 2011; 16: 992–1005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Abdel-rahmana SZ, El-zeinb RA, Anwa WA, Au WW . A multiplex PCR procedure for polymorphic analysis of GSTMl and GSTTl genes in population studies. Cancer Lett 1996; 107: 229–233.

    Article  Google Scholar 

  78. Ryu J-S, Hong Y-C, Han H-S, Lee J-E, Kim S, Park Y-M et al. Association between polymorphisms of ERCC1 and XPD and survival in non-small-cell lung cancer patients treated with cisplatin combination chemotherapy. Lung Cancer 2004; 44: 311–316.

    Article  PubMed  Google Scholar 

  79. Shen MR, Jones IM, Mohrenweiser H . Nonconservative amino acid substitution variants exist at polymorphic frequency in DNA repair genes in healthy humans1. Cancer Res 1998; 58: 604–609.

    CAS  PubMed  Google Scholar 

  80. Chen P, Wiencke J, Aldape K, Kesler-diaz A, Miike R, Kelsey K et al. Association of an ERCC1 polymorphism with adult-onset glioma 1. Cancer Epidemiol Biomarkers Prev 2000; 9: 843–847.

    CAS  PubMed  Google Scholar 

  81. Findlay JM, Middleton MR, Tomlinson I . A systematic review and meta-analysis of somatic and germline DNA sequence biomarkers of esophageal cancer survival, therapy response and stage. Ann Oncol 2015; 26: 624–644.

    Article  CAS  PubMed  Google Scholar 

  82. Benhamou S, Sarasin A . ERCC2/XPD gene polymorphisms and lung cancer: a HuGE review. Am J Epidemiol 2005; 161: 1–14.

    Article  PubMed  Google Scholar 

  83. Kuehl P, Zhang J, Lin Y, Lamba J, Assem M, Schuetz J et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet 2001; 27: 383–391.

    Article  CAS  PubMed  Google Scholar 

  84. Gréen H, Khan MS, Jakobsen-Falk I, Åvall-Lundqvist E, Peterson C . Impact of CYP3A5*3 and CYP2C8-HapC on paclitaxel/carboplatin-induced myelosuppression in patients with ovarian cancer. J Pharm Sci 2011; 100: 4205–4209.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We gratefully thank all patients who participated in the studies. The study was funded by the Netherlands Cancer Institute.

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  1. D Meulendijks and E A Rozeman: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    D Meulendijks & J H M Schellens

  2. Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    D Meulendijks, E A Rozeman & J H M Schellens

  3. Department of Gastroenterology and Hepatology, Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    D Meulendijks & A Cats

  4. Dutch Medicines Evaluation Board, Utrecht, The Netherlands

    D Meulendijks

  5. Department of Biometrics, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    K Sikorska

  6. Department of Medical Oncology and Hematology, Cantonal Hospital, St Gallen, Switzerland

    M Joerger & M J Deenen

  7. Department of Clinical Pharmacy, Catharina Hospital, Eindhoven, The Netherlands

    M J Deenen

  8. Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    J H Beijnen

  9. Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical Pharmacology, Faculty of Science, Utrecht University, Utrecht, The Netherlands

    J H Beijnen & J H M Schellens

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Meulendijks, D., Rozeman, E., Cats, A. et al. Pharmacogenetic variants associated with outcome in patients with advanced gastric cancer treated with fluoropyrimidine and platinum-based triplet combinations: a pooled analysis of three prospective studies. Pharmacogenomics J 17, 441–451 (2017). https://doi.org/10.1038/tpj.2016.81

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  • DOI: https://doi.org/10.1038/tpj.2016.81

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