Table 2: Overview of 33 additional SNPs located in genes involved in the pharmacokinetics or pharmacodynamics of the FEC regimen
Genes / Name / Function of the gene product / Variant allele (rs number, position, amino acid change) / Pharmacokinetic or pharmacodynamics effectABCBI/MDR1 / Multidrug resistance 1 / Drug transporter implicated in energy dependent transport of cytotoxic agents out of the cell / rs2032582 c.2677G>T/A Ala893Ser/Thr / Selected because missense mutations are likely to affect gene function.
NCF4* / Neutrophil cytosolic factor 4 / Component of the NADPH-oxidase, a multicomponent enzyme system responsible for the oxidative burst in which electrons are transported from NADPH to molecular oxygen, generating reactive oxidant intermediates. / rs1883112 g.-212A>G N/A / The rs1883112 SNP is responsible for downregulation of the NADPH-oxidase subunit NCF4 and has previously been associated with cardiotoxicity after anthracycline therapy (Wojnowski et al4).
ABCC2/MRP2 / Multidrug resistance-associated protein 2 / Drug transporter implicated in energy dependent transport of cytotoxic agents out of the cell / rs2804402 -1019T>C 5’-flanking
rs17222723 c.3563T>A Val1188Glu
rs2273697 c.1249G>A Val417Ile / Selected because missense mutations are likely to affect gene function.
DPD / Dihydropirymidine dehydrogenase / Enzyme involved in degradation of pyrimidine and uracil analogues during 5-FU chemotherapy / rs1801159 c.1627A>G Ile543Val
rs1801160 c.2194G>A Val732Ile
rs1801265 c.85T>C Cys29Arg / Selected because missense mutations are likely to affect gene function.
RAC2* / Ras-related C3 botulinum toxin substrate 2 / Plasma membrane-associated small GTPase that binds to a variety of effector proteins to regulate cellular responses. RAC2 augments the production of reactive oxygen species by NADPH oxidase / rs13058338 7508T>A N/A / This variant has previously been associated with cardiotoxicity after anthracycline therapy (Wojnowski et al4).
CYBA* / Cytochrome b-245, alpha polypeptide / Critical component of the membrane-bound oxidase of phagocytes that generates superoxide. CYBA associates with NOX3 to form a functional NADPH oxidase constitutively generating superoxide. / rs4673 c.214C>T His72Tyr / The rs4673 T-allele in CYBA, coding for p22phox, has previously been associated with cardiotoxicity after anthracycline therapy (Wojnowski et al4).
CYP3A4 / Cytochrome P450, family 3, subfamily A, polypeptide 4 / Enzyme involved in the activation pathway of cyclophosphamide by hydroxylating cyclophosphamide to 4-hydroxycyclophosphamide / rs4986910 c.1334T>C Met445Thr
rs55785340 c.664A>G Ser222Pro / Selected because missense mutations are likely to affect gene function.
SLC28A3* / Solute carrier family 28, member 3 / Sodium-dependent transporter involved in the homeostasis of endogenous nucleosides. / rs7853758 c.1381G>A Leu461Leu / This synonymous variant previously been associated with anthracycline-induced chemotherapy in children (Visscher et al3).
GSTA1 / Glutathione S-transferase alpha 1 / Enzyme involved in the detoxification of cyclophosphamide by conjugation of cyclophosphamide metabolites / rs3957356 g.52608670T>C N/A
rs3957357 -69G>A N/A / The rs3957357 was predictive for rituximab-CHOP outcome in large B-cell lymphoma (Rossi et al40).
GSTP1 / Gluthathione S-transferase pi 1 / Enzyme involved in the detoxification of cyclophosphamide by conjugation of cyclophosphamide metabolites / rs1138272 c.341C>T Ala114Val / The rs1138272 was predictive in the adjuvant and metastatic setting of colorectal cancer patients treated with the 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX4) regimen (Cecchin et al41).
ABCG2* / ATP-binding cassette, subfamily G, member 2 / Drug transporter implicated in energy dependent transport of cytotoxic agents out of the cell / rs2231137 c.34G>A Val12Met / Variant genotypes for rs2231137 in ABCG2 were associated with significantly improved survival and increased odds for toxicity after anthracycline-based therapy (Hampras et al42).
ALDH3A1* / Aldehyde dehydrogenase 3 family, member A1 / Enzyme involved in the detoxification pathway of cyclophosphamide by oxidation of aldophosphamide / rs2228100 c.985C>G Pro329Ala / In high dose cyclophosphamide treated patients, rs2228100 was associated with increased hemorrhagic cystitis (ekhart et al43).
CYP2C8* / Cytochrome P450, family 2, subfamily C, polypeptide 8 / Enzyme involved in the activation pathway of cyclophosphamide by hydroxylating cyclophosphamide to 4-hydroxycyclophosphamide / rs72558196 c.475delA Thr159 Frameshift
rs10509681 c.1196T>C Lys399Arg
rs11572080 c.416G>A Arg139Lys
rs56489507 c.792T>C/G Ile264Ile/Met / SNPs in CYP2C8 have been reported to have an impact on rosiglitazone intake and the urinary excretion of dihydroxyeicosatrienoic acids (Kirchheiner et al44).
CYP2C9* / Cytochrome P450, family 2, subfamily C, polypeptide 9 / Enzyme involved in the activation pathway of cyclophosphamide by hydroxylating cyclophosphamide to 4-hydroxycyclophosphamide / rs1057910 c.1075A>C Ile359Leu
rs1799853 c.430C>T Arg144Cys / In vitro studies have shown that the rs1057910 variant causes an Ile359Leu substitution in the catalytic site of the CYP2C9 enzyme and is less active than the wild-type allele (Bosch et al45).
CYP2C19* / Cytochrome P450, family 2, subfamily C, polypeptide 19 / Enzyme involved in the activation pathway of cyclophosphamide by hydroxylating cyclophosphamide to 4-hydroxycyclophosphamide / rs4244285 c.681G>A Pro227Pro
rs4986893 c.636G>A Trp212STOP / CYP2C19*2 was correlated with reduced cyclophosphamide elimination and had a higher probability of developing end-stage renal disease when treated with cyclophosphamide for lupus nephritis (Timm et al46 and Takada et al47). CYP2C19*2 was also correlated with tendency for longer cyclophosphamide half-life in 103 patients treated for non-Hodgkin’s lymphoma (Nakajima et al13).
CYP3A5* / Cytochrome P450, family 3, subfamily A, polypeptide 5 / Enzyme involved in the activation pathway of cyclophosphamide by hydroxylating cyclophosphamide to 4-hydroxycyclophosphamide / rs776746 c.219-237G>A Splice variant / The rs776746 SNP in CYP3A5 is the most common cause of loss of hepatic CYP3A5 expression, which results in protein truncation due to defective splicing and retention of an intronic site carrying a premature termination codon. Thus, only people with at least one CYP3A5*1 allele express functional CYP3A5 (Van Schaik et al 48).
XRCC1 / X-ray repair complementing defective repair in Chinese hamster cells 1 / The base excision repair protein capable to restore DNA single-strand breaks emerged due to exposure to ionizing radiation and alkylating agents / rs25489 c.839G>A Arg280His / Selected because missense mutations are likely to affect gene function.
UGT2B7* / UDP-glucuronosyltransferase 2 family, polypeptideB7 / Enzyme responsible for the formation of epirubicin glucuronide, which is the most important inactivation pathway of epirubicin / rs7439366 c.802T>C or UGT2B7*2
Tyr268His
rs7662029 -327A>G N/A
rs7668282 -79T>C N/A
rs12233719 c.211G>T or UGT2B7*3
Ala71Ser / UGT2B7 genetic polymorphisms are associated with the withdrawal symptoms in methadone maintenance patients (Tian et al49).
XRCC3* / X-ray repair complementing defective repair in Chinese hamster cells 3 / Involved in the homologous recombination repair pathway of double-stranded DNA, thought to repair chromosomal fragmentation, translocations and deletions / rs861534 g.104168701G>A N/A / The rs861534 SNP was associated with longer OS in early breast cancer patients receiving adjuvant chemotherapy. In the patient’s subgroup receiving anthracyclines XRCC3 rs861534 was associated with improved OS (Marcos et al50).
Legend to Table 2: The rs2273697, rs11572080, rs56489507 and rs3957356 SNPs failed genotyping on Sequenom MassARRAY. The rs861534 variant also failed, but was captured by genotyping the synonymous SNP rs861539. * Selection of extra genes based on current knowledge of genes involved in the metabolism of 5-fluorouracil, epirubicine, and cyclophosphamide (see also webappendix 2). SNP in DNA repair pathways, which are activated after DNA damage by chemotherapy, can potentially influence metabolism and toxicity but also efficacy of the chemotherapy.
Legend to Table 1 and 2:
The SNP selection for the FEC regimen has been extensively described in table 1 and 2 of our previous paper
Vulsteke C, Lambrechts D, Dieudonné AS et al: Genetic variability in the multidrug resistance associated protein-1 (ABCC1/MRP1) predicts hematological toxicity in breast cancer patients receiving (neo-) adjuvant chemotherapy with 5-fluorouracil, epirubicin and cyclophosphamide (FEC). Ann Oncol 24(6):1513-25, 2013.
References
1. Kafka A, Sauer G, Jaeger C et al: Polymorphism C3435T of the MDR-1 predicts response to preoperative chemotherapy in locally advanced breast cancer. Int J Oncol 22:1117-1121, 2003.
2. Semsei AF, erdelyi DJ, Ungvari I et al: ABCC1 polymorphisms in anthracycline induced cardiotoxicity in childhood acute lymphoblastic leukemia. Cell Biol Int 36 (1):79-86, 2012.
3. Visscher H, Ross CJ, Rassekh SR et al: Pharmacogenomic Prediction of Anthracycline-Induced Cardiotoxicity in Children. J Clin Onc 30(13):1422-8, 2012.
4. Wojnowski L, Kulle B, Schirmer M et al: NAD(P)H oxidase and multidrug resistance protein genetic polymorphisms are associated with doxorubicin-induced cardiotoxicity. Circulation 13; 112(24):3754-62, 2005.
5. Van Kuilenburg AB, Haasjes J, Richel DJ 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 6:4705-4712, 2000.
6. Van Kuilenburg AB: Dihydropyrimidine dehydrogenase and the efficacy and toxicity of 5-fluorouracil. Eur J Cancer 40:939-950, 2004.
7. Van Kuilenbrug AB, Muller EW, Haasjes J et al: Lethal outcome of a patient with a complete dihydropyrimidine dehydrogenase (DPD) deficiency after administration of 5-fluorouracil: frequency of the common IVS14+1G>A mutation causing DPD deficiency. Clin Cancer Res 7:1149-1153, 2001.
8. Takimoto CH, Lu ZH, Zhang R et al: Severe neurotoxicity following 5-fluorouracil-based chemotherapy in a patient with dihydropyrimidine dehydrogenase deficiency. Clin Cancer res 2:477-481, 1996.
9. Raida M, Schwabe W, Hausler P et al: Prevalence of a common point mutation in the dihydropyrimidine dehydrogenase (DPD) gene within the 5’-splice donor site of intron 14 in patients with severe 5-fluorouracil (5FU)-related toxicity compared with controls. Clin Cancer res 7:2832-2839, 2001.
10. Morel A, Boisdron-celle M, Fey L et al: Clinical relevance of different dihydropyrimidine dehydrogenase gene single nucleotide polymorphisms on 5-fluorouracil tolerance. Mol Cancer ther 5(11):2895-2904, 2006.
11. Sohn KJ, Croxford R, Yates Z et al: 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, 134-144, 2004.
12. Etienne-Grimaldi MC, Milano G, Maindrault-Goebel F et al: Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and FOLFOX response in colorectal cancer patients. Br J Clin Pharmacol 69(1): 58-66, 2010.
13. Nakajima M, Komagata S, Fujiki Y et al: Genetic polymorphisms of CYP2B6 affect the pharmacokinetics/pharmacodynamics of cyclophosphamide in japanese cancer patients. Pharmacogenet Genom 17(6):431-445, 2007.
14. Rocha V, Porcher R, Fernandes JF et al: Association of drug metabolism gene polymorphisms with toxicities, graft-versus-host disease and survival after HLA-identical sibling hematopoietic stem cell transplantation for patients with leukemia. Leukemia 23(3): 545-56, 2008.
15. Bray J, Sludden J, Griffin MJ et al: Influence of pharmacogentics on response and toxicity in breast cancer patients treated with doxorubicin and cyclophosphamide. Br J Cancer 102(6):1003-9, 2010.
16. Gor PP, Su HI, Gray RJ et al: Cyclophosphamide-metabolizing enzyme polymorphisms and survival outcomes after adjuvant chemotherapy for node-positive breast cancer: a retrospective cohort study. Breast Cancer Res 12(3):R26, 2010.
17. Udler M, Maia AT, Cebrian A et al: Common germline genetic variation in antioxidant defense genes and survival after diagnosis of breast cancer. J Clin Oncol 25(21): 3015-23, 2007.
18. Sweeney C, Ambrosone CB, Joseph L et al: Association between a glutathione S-transferase A1 promoter polymorphism and survival after breast cancer treatment. Int J Cancer 103(6): 810-4, 2003.
19. Zhong S, Huang M, Yang X et al: Relationship of glutathione S-transferase genotypes with side-effects of pulsed cyclophosphamide therapy in patients with systemic lupus erythematosus. Br J Clin Pharmacol 62(4): 457-72, 2006.
20. Thussbas C, Nahrig J, Streit S et al: FGFR4 Arg388 allele is associated with resistance to adjuvant therapy in primary breast cancer. J Clin Oncol 24(23): 3747-55, 2006.
21. Fagerholm R, Hofstetter B, Tommiska J et al: NAD(P)H: quinone oxidoreductase 1 NQO1*2 genotype (P187S) is a strong prognostic and predictive factor in breast cancer. Nat Genet 40(7):844-853, 2008.
22. Bewick MA, Conlon MS, Lafrenie RM et al: Polymorphisms in manganese superoxide dismutase, myeloperoxidase and glutathione-S-transferase and survival after treatment for metastatic breast cancer. Breast Cancer Res Treat 111, 93-101, 2008.
23. Marsh S, Mcleod HL: Thymidylate synthase pharmacogenetics in colorectal cancer. Clin Colorectal Cancer 1(3):175-8, 2001.
24. Sun Z, Chen J, Aakre J et al: Genetic variation in glutathione metabolism and DNA repair genes predicts survival of small-cell lung cancer patients. Ann Oncol 21(10): 2011-6, 2010.
25. Jaremko M, Justenhoven C, Schroth W et al: Polymorphism of the DNA repair enzyme XRCC1 is associated with treatment prediction in anthracycline and cyclophosphamide/methotrexate/5-fluorouracil-based chemotherapy of patients with primary invasive breast cancer. Pharmacogenet genomics 17(7): 529-38, 2007.
26. Lai JI, Tzeng CH, Chen PM et al: Very low prevalence of XPD K751Q polymorphism and its association with XPD expression and outcomes of FOLFOX-4 treatment in Asian patients with colorectal carcinoma. Cancer Sci 100(7):1261-6, 2009.
27. Khrunin AV, Moisseev A, Gorbunova V et al: Genetic polymorphisms and the efficacy and toxicity of cisplatin-based chemotherapy in ovarian cancer patients. Pharmacogenomics J 10(1):54-61, 2010.
28. Clarke L, Zheng-Bradley X, Smith R et al: The 1000 Genomes Project: data management and community access. Nat Methods 9(5):459-62, 2012.
29. Reumers J, De Rijk P, Zhao H et al: Optimized filtering reduces the error rate in detecting genomic variants by short-read sequencing. Nat Biotechnol 30 (1):61-8, 2011.
30. Sun L, Craiu RV, Paterson AD et al: Stratified false discovery control for large-scale hypothesis testing with application to genome-wide association studies. Genet Epidemiol 30(6):519-30, 2006.
31. Dean, M., Rzhetsky, A., & Allikmets, R. (2001). The human ATP-binding cassette (ABC) transporter superfamily. Genome Research, 11:1156–1166, 2001.
32. Cole SP, Bhardwaj G, Gerlach, JH, Mackie, JE et al: Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science, 258: 1650–1654, 1992.
33. Flens MJ, Zaman GJ, van der Valk P et al: Tissue distribution of the multidrug resistance protein. American Journal of Pathology, 148:1237–1247, 1996.
34. Zhou SF, Wang LL, Di YM et al: Substrates and inhibitors of human multidrug resistance associated proteins and the implications in drug development. Curr Med Chem 15(20):1981-2039, 2008.
35. Wu Z, Li X, Zeng Y et al: In vitro and in vivo inhibition of MRP gene expression and reversal of multidrug resistance by siRNA. Basic Clin Pharmacol Toxicol 108(3):177-184, 2011.
36. Jungsuwadee P, Zhao T, Stolarczyk El et al: The G671V variant of MRP1/ABCC1 links doxorubicin-induced acute cardiac toxicity to disposition of the glutathione conjugate of 4-hydroxy-2-trans-nonenal. Pharmacogenet Genomics 22 (4):273-84, 2012.
37. Aapro MS, Bohlius J, Cameron DA et al: 2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours. Eur J Cancer, 47(1):8-32, 2011.