Pharmacogenetic variants in the DPYD, TYMS, CDA and MTHFR genes are clinically significant predictors of fluoropyrimidine toxicity

British Journal of Cancer

Volumn 108, Issue 12, 2013, Pages 2505-2515

  Loganayagam, A ^a   Arenas Hernandez, M ^a   Corrigan, A ^a   Fairbanks, L ^a   Lewis, C M ^b   Harper, P ^c   Maisey, N ^c   Ross, P ^c   Sanderson, J D ^a   Marinaki, A M ^a  

^a ST THOMAS HOSPITAL   (United Kingdom)

^b KING'S COLLEGE LONDON   (United Kingdom)

^c GUY S HOSPITAL   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

5,10 METHYLENETETRAHYDROFOLATE REDUCTASE (FADH2); CAPECITABINE; CISPLATIN; CYTIDINE DEAMINASE; DIHYDROPYRIMIDINE DEHYDROGENASE; EPIRUBICIN; FLUOROPYRIMIDINE DERIVATIVE; FLUOROURACIL; FOLINIC ACID; IRINOTECAN; MITOMYCIN; OXALIPLATIN; PROTEIN; TYMS PROTEIN; UNCLASSIFIED DRUG;

3' UNTRANSLATED REGION; ADULT; AGED; AMINO ACID SUBSTITUTION; ARTICLE; CANCER COMBINATION CHEMOTHERAPY; DIARRHEA; FEMALE; GENE FREQUENCY; GENE SEQUENCE; GENETIC ASSOCIATION; GENETIC RISK; GENETIC VARIABILITY; GENOTOXICITY; GENOTYPE; HAND FOOT SYNDROME; HOMOZYGOSITY; HUMAN; MAJOR CLINICAL STUDY; MALE; MUCOSA INFLAMMATION; MULTIPLE CYCLE TREATMENT; NEUTROPENIA; PHARMACOGENETICS; PRIORITY JOURNAL; PROMOTER REGION; SINGLE NUCLEOTIDE POLYMORPHISM;

ADULT; AGED; AGED, 80 AND OVER; ANTIMETABOLITES, ANTINEOPLASTIC; CYTIDINE DEAMINASE; DIHYDROURACIL DEHYDROGENASE (NADP); DRUG TOXICITY; FEMALE; FLUOROURACIL; GENETIC VARIATION; HUMANS; MALE; METHYLENETETRAHYDROFOLATE REDUCTASE (NADPH2); MIDDLE AGED; MODELS, GENETIC; NEOPLASMS; PHARMACOGENETICS; PROGNOSIS; RISK FACTORS; THYMIDYLATE SYNTHASE; YOUNG ADULT;

EID: 84879688848     PISSN: 00070920     EISSN: 15321827     Source Type: Journal    
DOI: 10.1038/bjc.2013.262     Document Type: Article

References (48)

1. Afzal S, Jensen SA, Vainer B, Vogel U, Matsen JP, Sorensen JB, Andersen PK, Poulsen HE (2009) MTHFR polymorphisms and 5-FU-based adjuvant chemotherapy in colorectal cancer. Ann Oncol 20(10): 1660-1666.
2. Amstutz U, Farese S, Aebi S, Largiader CR (2009) Dihydropyrimidine dehydrogenase gene variation and severe 5-fluorouracil toxicity: a haplotype assessment. Pharmacogenomics 10(6): 931-944.
3. Amstutz U, Froehlich TK, Largiader CR (2011) Dihydropyrimidine dehydrogenase gene as a major predictor of severe 5-fluorouracil toxicity. Pharmacogenomics 12(9): 1321-1336.
4. Braun MS, Richman SD, Thompson L, Daly CL, Meade AM, Adlard JW, Allan JM, Parmar MK, Quirke P, Seymour MT (2009) Association of molecular markers with toxicity outcomes in a randomized trial of chemotherapy for advanced colorectal cancer: the FOCUS trial. J Clin Oncol 27(33): 5519-5528.
5. Cancer M-AGI (1998) Toxicity of fluorouracil in patients with advanced colorectal cancer: effect of administration schedule and prognostic factors. J Clin Oncol 16: 3537-3541.
6. Caronia D, Martin M, Sastre J, de la Torre J, Garcia-Saenz JA, Alonso MR, Moreno LT, Pita G, Diaz-Rubio E, Benitez J, Gonzalez-Neira A (2011) A polymorphism in the cytidine deaminase promoter predicts severe capecitabine-induced hand-foot syndrome. Clin Cancer Res 17(7): 2006-2013.
7. Castillo-Fernandez O, Santibanez M, Bauza A, Calderillo G, Castro C, Herrera R, Serrano A, Arrieta O, Herrera LA (2010) Methylenetetrahydrofolate reductase polymorphism (677 C4T) predicts long time to progression in metastatic colon cancer treated with 5-fluorouracil and folinic acid Arch Med Res 41(6): 430-435.
8. Cohen V, Panet-Raymond V, Sabbaghian N, Morin I, Batist G, Rozen R (2003) Methylenetetrahydrofolate reductase polymorphism in advanced colorectal cancer: a novel genomic predictor of clinical response to fluoropyrimidine-based chemotherapy. Clin Cancer Res 9(5): 1611-1615.
9. Collie-Duguid ES, Etienne MC, Milano G, McLeod HL (2000) Known variant DPYD alleles do not explain DPD deficiency in cancer patients. Pharmacogenetics 10(3): 217-223.
10. De Mattia E, Toffoli G (2009) C677T and A1298C MTHFR polymorphisms, a challenge for antifolate and fluoropyrimidine-based therapy personalisation. Eur J Cancer 45(8): 1333-1351.
11. Deenen MJ, Tol J, Burylo AM, Doodeman VD, de Boer A, Vincent A, Guchelaar HJ, Smits PH, Beijnen JH, Punt CJ, Schellens JH, Cats A (2011) Relationship between single nucleotide polymorphisms and haplotypes in DPYD and toxicity and efficacy of capecitabine in advanced colorectal cancer. Clin Cancer Res 17(10): 3455-3468.
12. Ezzeldin H, Diasio R (2004) Dihydropyrimidine dehydrogenase deficiency, a pharmacogenetic syndrome associated with potentially life-threatening toxicity following 5-fluorouracil administration. Clin Colorectal Cancer 4(3): 181-189.
13. Ezzeldin HH, Diasio RB (2008) Predicting fluorouracil toxicity: can we finally do it? J Clin Oncol 26(13): 2080-2082.
14. Fidlerova J, Kleiblova P, Bilek M, Kormunda S, Formankova Z, Novotny J, Kleibl Z (2010) Contribution of dihydropyrimidinase gene alterations to the development of serious toxicity in fluoropyrimidine-treated cancer patients. Cancer Chemother Pharmacol 65(4): 661-669.
15. Fitzgerald SM, Goyal RK, Osborne WR, Roy JD, Wilson JW, Ferrell RE (2006) Identification of functional single nucleotide polymorphism haplotypes in the cytidine deaminase promoter. Hum Genet 119(3): 276-283.
16. Gilbert JA, Salavaggione OE, Ji Y, Pelleymounter LL, Eckloff BW, Wieben ED, Ames MM, Weinshilboum RM (2006) Gemcitabine pharmacogenomics: cytidine deaminase and deoxycytidylate deaminase gene resequencing and functional genomics. Clin Cancer Res 12(6): 1794-1803.
17. Gross E, Busse B, Riemenschneider M, Neubauer S, Seck K, Klein HG, Kiechle M, Lordick F, Meindl A (2008) Strong association of a common dihydropyrimidine dehydrogenase gene polymorphism with fluoropyrimidine-related toxicity in cancer patients. PLoS One 3(12): e4003.
18. Gross E, Ullrich T, Seck K, Mueller V, de Wit M, von Schilling C, Meindl A, Schmitt M, Kiechle M (2003) Detailed analysis of five mutations in dihydropyrimidine dehydrogenase detected in cancer patients with 5-fluorouracil-related side effects. Hum Mutat 22(6): 498.
19. Gusella M, Frigo AC, Bolzonella C, Marinelli R, Barile C, Bononi A, Crepaldi G, Menon D, Stievano L, Toso S, Pasini F, Ferrazzi E, Padrini R (2009) Predictors of survival and toxicity in patients on adjuvant therapy with 5-fluorouracil for colorectal cancer. Br J Cancer 100(10): 1549-1557.
20. Hamajima N, Kouwaki M, Vreken P, Matsuda K, Sumi S, Imaeda M, Ohba S, Kidouchi K, Nonaka M, Sasaki M, Tamaki N, Endo Y, De Abreu R, Rotteveel J, van Kuilenburg A, van Gennip A, Togari H, Wada Y (1998) Dihydropyrimidinase deficiency: structural organization, chromosomal localization, and mutation analysis of the human dihydropyrimidinase gene. Am J Hum Genet 63(3): 717-726.
21. Hameed H, Cassidy J (2011) Use of capecitabine in management of early colon cancer. Cancer Manag Res 3: 295-299.
22. Horie N, Aiba H, Oguro K, Hojo H, Takeishi K (1995) 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 20(3): 191-197.
23. Jennings BA, Kwok CS, Willis G, Matthews V, Wawruch P, Loke YK (2012) Functional polymorphisms of folate metabolism and response to chemotherapy for colorectal cancer, a systematic review and meta-analysis. Pharmacogenet Genomics 22(4): 290-304.
24. 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(18): 6004-6007.
25. Largillier R, Etienne-Grimaldi MC, Formento JL, Ciccolini J, Nebbia JF, Ginot A, Francoual M, Renee N, Ferrero JM, Foa C, Namer M, Lacarelle B, Milano G (2006) Pharmacogenetics of capecitabine in advanced breast cancer patients. Clin Cancer Res 12(18): 5496-5502.
26. Lecomte T, Ferraz JM, Zinzindohoue F, Loriot MA, Tregouet DA, Landi B, Berger A, Cugnenc PH, Jian R, Beaune P, Laurent-Puig P (2004) Thymidylate synthase gene polymorphism predicts toxicity in colorectal cancer patients receiving 5-fluorouracil-based chemotherapy. Clin Cancer Res 10(17): 5880-5888.
27. Lincz LF, Scorgie FE, Garg MB, Ackland SP (2007) Identification of a novel single nucleotide polymorphism in the first tandem repeat sequence of the thymidylate synthase 2R allele. Int J Cancer 120(9): 1930-1934.
28. Loganayagam A, Arenas-Hernandez M, Fairbanks L, Ross P, Sanderson JD, Marinaki AM (2010) The contribution of deleterious DPYD gene sequence variants to fluoropyrimidine toxicity in British cancer patients. Cancer Chemother Pharmacol 65(2): 403-406.
29. Lurje G, Manegold PC, Ning Y, Pohl A, Zhang W, Lenz HJ (2009) Thymidylate synthase gene variations: predictive and prognostic markers. Mol Cancer Ther 8(5): 1000-1007.
30. Mandola MV, Stoehlmacher J, Muller-Weeks S, Cesarone G, Yu MC, Lenz HJ, Ladner RD (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.
31. Mandola MV, Stoehlmacher J, Zhang W, Groshen S, Yu MC, Iqbal S, Lenz HJ, Ladner RD (2004) A 6 bp polymorphism in the thymidylate synthase gene causes message instability and is associated with decreased intratumoral TS mRNA levels. Pharmacogenetics 14(5): 319-327.
32. Mercier C, Dupuis C, Blesius A, Fanciullino R, Yang CG, Padovani L, Giacometti S, Frances N, Iliadis A, Duffaud F, Ciccolini J (2009) Early severe toxicities after capecitabine intake: possible implication of a cytidine deaminase extensive metabolizer profile. Cancer Chemother Pharmacol 63(6): 1177-1180.
33. Milano G, Etienne-Grimaldi MC, Mari M, Lassalle S, Formento JL, Francoual M, Lacour JP, Hofman P (2008) Candidate mechanisms for capecitabine-related hand-foot syndrome. Br J Clin Pharmacol 66(1): 88-95.
34. Morel A, Boisdron-Celle M, Fey L, Soulie P, Craipeau MC, Traore S, Gamelin E (2006) Clinical relevance of different dihydropyrimidine dehydrogenase gene single nucleotide polymorphisms on 5-fluorouracil tolerance. Mol Cancer Ther 5(11): 2895-2904.
35. Pinedo HM, Peters GF (1988) Fluorouracil: biochemistry and pharmacology. J Clin Oncol 6(10): 1653-1664.
36. Ribelles N, Lopez-Siles J, Sanchez A, Gonzalez E, Sanchez MJ, Carabantes F, Sanchez-Rovira P, Marquez A, Duenas R, Sevilla I, Alba E (2008) A carboxylesterase 2 gene polymorphism as predictor of capecitabine on response and time to progression. Curr Drug Metab 9(4): 336-343.
37. Ruzzo A, Graziano F, Loupakis F, Rulli E, Canestrari E, Santini D, Catalano V, Ficarelli R, Maltese P, Bisonni R, Masi G, Schiavon G, Giordani P, Giustini L, Falcone A, Tonini G, Silva R, Mattioli R, Floriani I, Magnani M (2007) Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFOX-4 chemotherapy. J Clin Oncol 25(10): 1247-1254.
38. Ruzzo A, Graziano F, Loupakis F, Santini D, Catalano V, Bisonni R, Ficarelli R, Fontana A, Andreoni F, Falcone A, Canestrari E, Tonini G, Mari D, Lippe P, Pizzagalli F, Schiavon G, Alessandroni P, Giustini L, Maltese P, Testa E, Menichetti ET, Magnani M (2008) Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFIRI chemotherapy. Pharmacogenomics J 8(4): 278-288.
39. Schwab M, Zanger UM, Marx C, Schaeffeler E, Klein K, Dippon J, Kerb R, Blievernicht J, Fischer J, Hofmann U, Bokemeyer C, Eichelbaum M (2008) 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 26(13): 2131-2138.
40. Seck K, Riemer S, Kates R, Ullrich T, Lutz V, Harbeck N, Schmitt M, Kiechle M, Diasio R, Gross E (2005) Analysis of the DPYD gene implicated in 5-fluorouracil catabolism in a cohort of Caucasian individuals. Clin Cancer Res 11(16): 5886-5892.
41. Sharma R, Hoskins JM, Rivory LP, Zucknick M, London R, Liddle C, Clarke SJ (2008) Thymidylate synthase and methylenetetrahydrofolate reductase gene polymorphisms and toxicity to capecitabine in advanced colorectal cancer patients. Clin Cancer Res 14(3): 817-825.
42. Thorn CF, Marsh S, Carrillo MW, McLeod HL, Klein TE, Altman RB (2011) PharmGKB summary: fluoropyrimidine pathways. Pharmacogenet Genomics 21(4): 237-242.
43. van Kuilenburg AB, Dobritzsch D, Meinsma R, Haasjes J, Waterham HR, Nowaczyk MJ, Maropoulos GD, Hein G, Kalhoff H, Kirk JM, Baaske H, Aukett A, Duley JA, Ward KP, Lindqvist Y, van Gennip AH (2002) Novel disease-causing mutations in the dihydropyrimidine dehydrogenase gene interpreted by analysis of the three-dimensional protein structure. Biochem J 364(Pt 1): 157-163.
44. van Kuilenburg AB, Hausler P, Schalhorn A, Tanck MW, Proost JH, Terborg C, Behnke D, Schwabe W, Jabschinsky K, Maring JG (2012) Evaluation of 5-fluorouracil pharmacokinetics in cancer patients with a c.1905 +1G4A mutation in DPYD by means of a Bayesian limited sampling strategy. Clin Pharmacokinet 51(3): 163-174.
45. van Kuilenburg AB, Meijer J, Mul AN, Meinsma R, Schmid V, Dobritzsch D, Hennekam RC, Mannens MM, Kiechle M, Etienne-Grimaldi MC, Klumpen HJ, Maring JG, Derleyn VA, Maartense E, Milano G, Vijzelaar R, Gross E (2010) 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 128(5): 529-538.
46. van Kuilenburg AB, Meinsma R, Zonnenberg BA, Zoetekouw L, Baas F, Matsuda K, Tamaki N, van Gennip AH (2003) Dihydropyrimidinase deficiency and severe 5-fluorouracil toxicity. Clin Cancer Res 9(12): 4363-4367.
47. Walko CM, Lindley C (2005) Capecitabine: a review. Clin Ther 27(1): 23-44.
48. Yang CG, Ciccolini J, Blesius A, Dahan L, Bagarry-Liegey D, Brunet C, Varoquaux A, Frances N, Marouani H, Giovanni A, Ferri-Dessens RM, Chefrour M, Favre R, Duffaud F, Seitz JF, Zanaret M, Lacarelle B, Mercier C (2011) DPD-based adaptive dosing of 5-FU in patients with head and neck cancer: impact on treatment efficacy and toxicity. Cancer Chemother Pharmacol 67(1): 49-56.