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Toll-like receptor/interleukin-1 domain innate immune signalling pathway genetic variants are candidate predictors for severe gastrointestinal toxicity risk following 5-fluorouracil-based chemotherapy

  • Samantha K. KorverEmail author
  • Rachel J. Gibson
  • Joanne M. Bowen
  • Janet K. Coller
Review Article

Abstract

Purpose

Severe gastrointestinal (GI) toxicity is a common adverse effect following 5-fluorouracil (5-FU)-based chemotherapy treatment. The presence of severe GI toxicity leads to treatment revisions, sub-optimal therapy outcomes, and decreases to patients’ quality of life. There are no adequate predictors for 5-FU-induced severe GI toxicity risk. The Toll-like receptor/interleukin-1 (TIR) domain innate immune signalling pathway is known to be a mediating pathway in the development of GI toxicity. Hence, genetic variability in this signalling pathway may alter the pathophysiology of GI toxicity and, therefore, be predictive of risk. However, little research has investigated the effects of TIR domain innate immune signalling pathway single nucleotide polymorphism (SNPs) on the risk and development of severe GI toxicity.

Methods

This critical review surveyed the literature and reported on the in vitro, ex vivo and in vivo effects, as well as the genetic association, of selected TIR domain innate immune signalling pathway SNPs on disease susceptibility and gene functioning.

Results

Of the TIR domain innate immune signalling pathway SNPs reviewed, evidence suggests interleukin-1 beta (IL1B) and tumour necrosis factor alpha (TNF) SNPs have the greatest potential as predictors for severe GI toxicity risk. These results warrant further research into the effect of IL1B and TNF SNPs on the risk and development of severe GI toxicity.

Conclusions

SNPs of the TIR domain innate immune signalling pathway have profound effects on disease susceptibility and gene functioning, making them candidate predictors for severe GI toxicity risk. The identification of a predictor for 5-FU-induced severe GI toxicity will allow the personalization of supportive care measures.

Keywords

5-Fluorouracil (5-FU) Gastrointestinal (GI) toxicity Toll-like receptors (TLRs) Proinflammatory cytokines Single nucleotide polymorphisms (SNPs) Genetic variant 

Abbreviations

5-FU

5-fluorouracil

DAMPs

Damage associated molecular patterns

DPD

Dihydropyrimidine dehydrogenase enzyme

DPYD

Dihydropyrimidine dehydrogenase gene

GI

Gastrointestinal

HSCT

Hematopoietic stem cell transplantation

IKK

Inhibitor of NF-κB-kinase complex

IRAK1

Interleukin-1 receptor-associated kinases 1

IRAK4

Interleukin-1 receptor-associated kinases 4

MYD88

Myeloid differentiation primary response protein 88

NCI CTCAE v5.0

The National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0

PAMPs

Pathogen associated molecular patterns

PBMCs

Peripheral blood mononuclear cells

SNPs

Single nucleotide polymorphisms

TAB1

Tak-1 binding protein 1

TAB2

Tak-1 binding protein 2

TAK1

Transforming growth factor beta factor-β activated kinase 1

TIR

Toll-like receptor/interleukin-1

TLR

Toll-like receptor

TRAF6

TNF receptor associated factor 6

Notes

Funding

Samantha Korver is funded by a Research Training Program Scholarship and Doctor Chun Chung Wong and Madam So Sau Lam Memorial Postgraduate Cancer Research Scholarship.

Compliance with ethical standards

Conflict of interest

Samantha Korver declares she has no conflict of interest. Rachel Gibson is a consultant for Kaleido Biosciences, Mundipharma and Onyx Pharmaceuticals, and has received research funding from Onyx Pharmaceuticals and AstraZeneca. Joanne Bowen has received research funding from AstraZeneca, Helsinn, Pfizer and Puma Biotechnology Inc. Janet Coller declares she has no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

References

  1. 1.
    Longley DB, Harkin DP, Johnston PG (2003) 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 3:330–338PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Ezzeldin H, Diasio R (2004) Dihydropyrimidine dehydrogenase deficiency, a pharmacogenetic syndrome associated with potentially life-threatening toxicity following 5-fluorouracil administration. Clin Colorectal Cancer 4:181–189PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, Jandik P, Iveson T, Carmichael J, Alakl M, Gruia G, Awad L, Rougier P (2000) Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 355:1041–1047CrossRefGoogle Scholar
  4. 4.
    Giacchetti S, Perpoint B, Zidani R, Le Bail N, Faggiuolo R, Focan C, Chollet P, Llory JF, Letourneau Y, Coudert B, Bertheaut-Cvitkovic F, Larregain-Fournier D, Le Rol A, Walter S, Adam R, Misset JL, Levi F (2000) Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 18:136–147PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Logan RM, Stringer AM, Bowen JM, Gibson RJ, Sonis ST, Keefe DM (2009) Is the pathobiology of chemotherapy-induced alimentary tract mucositis influenced by the type of mucotoxic drug administered? Cancer Chemother Pharmacol 63:239–251PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Keefe D, Brealey J, Goland G, Cummins A (2000) Chemotherapy for cancer causes apoptosis that precedes hypoplasia in crypts of the small intestine in humans. Gut 47:632–637PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Sonis ST (2004) The pathobiology of mucositis. Nat Rev Cancer 4:277–284PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Sonis ST, Elting LS, Keefe D, Peterson DE, Schubert M, Hauer-Jensen M, Bekele BN, Raber-Durlacher J, Donnelly JP, Rubenstein, EB & Mucositis Study Section of the Multinational Association for Supportive Care in Cancer; International Society for Oral Oncology (2004) Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients. Cancer 100:1995–2025PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Lalla RV, Bowen J, Barasch A, Elting L, Epstein J, Keefe DM, McGuire DB, Migliorati C, Nicolatou-Galitis O, Peterson DE, Raber-Durlacher JE, Sonis ST, Elad S, The Mucositis Guidelines Leadership Group of the Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology (MASCC/ISOO) (2014) MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer 120:1453–1461PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Olver I, Ruhlmann CH, Jahn F, Schwartzberg L, Rapoport B, Rittenberg CN, Clark-Snow R (2016) 2016 Updated MASCC/ESMO Consensus Recommendations: Controlling nausea and vomiting with chemotherapy of low or minimal emetic potential. Support Care Cancer 25:297–301PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Capitain O, Boisdron-Celle M, Poirier AL, Abadie-Lacourtoisie S, Morel A, Gamelin E (2008) The influence of fluorouracil outcome parameters on tolerance and efficacy in patients with advanced colorectal cancer. Pharmacogenom J 8:256–267CrossRefGoogle Scholar
  12. 12.
    Sonis ST (2002) The biologic role for nuclear factor-kappaB in disease and its potential involvement in mucosal injury associated with anti-neoplastic therapy. Crit Rev Oral Biol Med 13:380–389PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Sonis ST (2004) A biological approach to mucositis. J Support Oncol 2:21–32PubMedPubMedCentralGoogle Scholar
  14. 14.
    Stringer AM, Al-Dasooqi N, Bowen JM, Tan TH, Radzuan M, Logan RM, Mayo B, Keefe DMK, Gibson RJ (2013) Biomarkers of chemotherapy-induced diarrhoea: a clinical study of intestinal microbiome alterations, inflammation and circulating matrix metalloproteinases. Support Care Cancer 21:1843–1852PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Rutman RJ, Cantarow A, Paschkis KE (1954) Studies in 2-Acetylaminofluorene Carcinogenesis. III. The utilization of uracil-2-C14 by preneoplastic rat liver and rat hepatoma. Cancer Res 14:119–123PubMedPubMedCentralGoogle Scholar
  16. 16.
    Diasio RB, Harris BE (1989) Clinical pharmacology of 5-fluorouracil. Clin Pharmacokinet 16:215–237PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Thorn CF, Marsh S, Carrillo MW, McLeod HL, Klein TE, Altman RB (2011) PharmGKB summary: fluoropyrimidine pathways. Pharmacogenet Genom 21:237–242Google Scholar
  18. 18.
    Miwa M, Ura M, Nishida M, Sawada N, Ishikawa T, Mori K, Shimma N, Umeda I, Ishitsuka H (1998) Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer 34:1274–1281PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Quinney SK, Sanghani SP, Davis WI, Hurley TD, Sun Z, Murry DJ, Bosron WF (2005) Hydrolysis of capecitabine to 5′-deoxy-5-fluorocytidine by human carboxylesterases and inhibition by loperamide. J Pharmacol Exp Ther 313:1011–1016PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Brody JR, Hucl T, Costantino CL, Eshleman JR, Gallmeier E, Zhu H, van der Heijden MS, Winter JM, Wikiewicz AK, Yeo CJ (2009) Limits to thymidylate synthase and TP53 genes as predictive determinants for fluoropyrimidine sensitivity and further evidence for RNA-based toxicity as a major influence. Cancer Res 69:984–991PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Noordhuis P, Holwerda U, Van der Wilt CL, Van Groeningen CJ, Smid K, Meijer S, Pinedo HM, Peters GJ (2004) 5-Fluorouracil incorporation into RNA and DNA in relation to thymidylate synthase inhibition of human colorectal cancers. Ann Oncol 15:1025–1032PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Fleming RA, Milano G, Thyss A, Etienne MC, Renee N, Schneider M, Demard F (1992) Correlation between dihydropyrimidine dehydrogenase activity in peripheral mononuclear cells and systemic clearance of fluorouracil in cancer patients. Cancer Res 52:2899–2902PubMedPubMedCentralGoogle Scholar
  23. 23.
    Cancer Institute New South Wales (2017) eviQ. New South Wales Government. https://www.eviq.org.au/. Accessed 7 May 2018
  24. 24.
    McKendrick J, Coutsouvelis J (2005) Capecitabine: effective oral fluoropyrimidine chemotherapy. Expert Opin Pharmacother 6:1231–1239PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Boussios S, Pentheroudakis G, Katsanos K, Pavlidis N (2012) Systemic treatment-induced gastrointestinal toxicity: incidence, clinical presentation and management. Ann Gastroenterol 25:106–118PubMedPubMedCentralGoogle Scholar
  26. 26.
    Villa A, Sonis ST (2015) Mucositis: pathobiology and management. Curr Opin Oncol 27:159–164PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    National Cancer Institute (2017) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. U.S. Department of Health and Human Services. https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_5x7.pdf. Accessed 5 May 2018
  28. 28.
    Franklin HR, Simonetti GP, Dubbelman AC, ten Bokkel Huinink WW, Taal BG, Wigbout G, Mandjes IA, Dalesio OB, Aaronson NK (1994) Toxicity grading systems. A comparison between the WHO scoring system and the Common Toxicity Criteria when used for nausea and vomiting. Ann Oncol 5:113–117PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Rubenstein EB, Peterson DE, Schubert M, Keefe D, McGuire D, Epstein J, Elting LS, Fox PC, Cooksley C, Sonis ST, Mucositis Study Section of the Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology (2004) Clinical practice guidelines for the prevention and treatment of cancer therapy-induced oral and gastrointestinal mucositis. Cancer 100: 2026–2046PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Keefe DM, Schubert MM, Elting LS, Sonis ST, Epstein JB, Raber-Durlacher JE, Migliorati CA, McGuire DB, Hutchins RD, Peterson DE, for the Mucositis Study Section of the Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology the International Society for Oral Oncology (2007) Updated clinical practice guidelines for the prevention and treatment of mucositis. Cancer 109: 820–831PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Einhorn LH, Rapoport B, Navari RM, Herrstedt J, Brames MJ (2017) 2016 updated MASCC/ESMO consensus recommendations: prevention of nausea and vomiting following multiple-day chemotherapy, high-dose chemotherapy, and breakthrough nausea and vomiting. Support Care Cancer 25:303–308PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Lee HR, Yoo N, Jeong J, Sohn KY, Yoon SY, Kim JW (2018) PLAG alleviates chemotherapy-induced thrombocytopenia via promotion of megakaryocyte/erythrocyte progenitor differentiation in mice. Thromb Res 161:84–90PubMedCrossRefGoogle Scholar
  33. 33.
    Meta-Analysis Group in Cancer, Levy E, Piedbois P, Buyse M, Pignon JP, Rougier P, Ryan L, Hansen R, Zee B, Weinerman B, Pater J, Leichman C, Macdonald J, Benedetti J, Lokich J, Fryer J, Brufman G, Isacson R, Laplanche A, Quinaux E, Thirion P (1998) Toxicity of fluorouracil in patients with advanced colorectal cancer: effect of administration schedule and prognostic factors. J Clin Oncol 16: 3537–3541CrossRefGoogle Scholar
  34. 34.
    Aprile G, Ramoni M, Keefe D, Sonis S (2008) Application of distance matrices to define associations between acute toxicities in colorectal cancer patients receiving chemotherapy. Cancer 112:284–292PubMedCrossRefGoogle Scholar
  35. 35.
    Carlotto A, Hogsett VL, Maiorini EM, Razulis JG, Sonis ST (2013) The economic burden of toxicities associated with cancer treatment: review of the literature and analysis of nausea and vomiting, diarrhoea, oral mucositis and fatigue. Pharmacoeconomics 31:753–766PubMedCrossRefGoogle Scholar
  36. 36.
    An Q, Robins P, Lindahl T, Barnes DE (2007) 5-Fluorouracil incorporated into DNA is excised by the Smug1 DNA glycosylase to reduce drug cytotoxicity. Cancer Res 67:940–945PubMedCrossRefGoogle Scholar
  37. 37.
    Rubartelli A, Lotze MT Inside, outside, upside down: damage-associated molecular-pattern molecules (DAMPs) and redox. Trends Immunol 28: 429–436PubMedCrossRefGoogle Scholar
  38. 38.
    Sonis ST (2007) Pathobiology of oral mucositis: novel insights and opportunities. J Support Oncol 5:3–11PubMedGoogle Scholar
  39. 39.
    Logan RM, Stringer AM, Bowen JM, Gibson RJ, Sonis ST, Keefe DM (2008) Serum levels of NFkappaB and pro-inflammatory cytokines following administration of mucotoxic drugs. Cancer Biol Ther 7:1139–1145PubMedCrossRefGoogle Scholar
  40. 40.
    Wardill HR, Van Sebille YZ, Mander KA, Gibson RJ, Logan RM, Bowen JM, Sonis ST (2015) Toll-like receptor 4 signaling: a common biological mechanism of regimen-related toxicities: an emerging hypothesis for neuropathy and gastrointestinal toxicity. Cancer Treat Rev 41:122–128PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Akira S, Takeda K (2004) Toll-like receptor signalling. Nat Rev Immunol 4:499–511PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Slack JL, Schooley K, Bonnert TP, Mitcham JL, Qwarnstrom EE, Sims JE, Dower SK (2000) Identification of two major sites in the type I interleukin-1 receptor cytoplasmic region responsible for coupling to pro-inflammatory signaling pathways. J Biol Chem 275:4670–4678PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Bell JK, Mullen GE, Leifer CA, Mazzoni A, Davies DR, Segal DM (2003) Leucine-rich repeats and pathogen recognition in Toll-like receptors. Trends Immunol 24:528–533PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Cario E (2013) Microbiota and innate immunity in intestinal inflammation and neoplasia. Curr Opin Gastroenterol 29:85–91PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Kawai T, Akira S (2009) The roles of TLRs, RLRs and NLRs in pathogen recognition. Int Immunol 21:317–337PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Takeda K, Akira S (2015) Toll-like receptors. Curr Protoc Immunol 109:1–14Google Scholar
  47. 47.
    Cario E (2016) Toll-like receptors in the pathogenesis of chemotherapy-induced gastrointestinal toxicity. Curr Opin Support Palliat Care 10:157–164PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Makarov SS (2000) NF-kappaB as a therapeutic target in chronic inflammation: recent advances. Mol Med Today 6:441–448PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Tak PP, Firestein GS (2001) NF-κB: a key role in inflammatory diseases. J Clin Investig 107:7–11PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Pahl HL (1999) Activators and target genes of Rel/NF-κB transcription factors. Oncogene 18:6853–6866PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Apte RN, Voronov E (2008) Is interleukin-1 a good or bad ‘guy’in tumor immunobiology and immunotherapy? Immunol Rev 222:222–241PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Hehlgans T, Pfeffer K (2005) The intriguing biology of the tumour necrosis factor/tumour necrosis factor receptor superfamily: players, rules and the games. Immunology 115:1–20PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Mocellin S, Rossi CR, Pilati P, Nitti D (2005) Tumor necrosis factor, cancer and anticancer therapy. Cytokine Growth Factor Rev 16:35–53PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Amstutz U, Henricks LM, Offer SM, Barbarino J, Schellens JHM, Swen JJ, Klein TE, McLeod HL, Caudle KE, Diasio RB, Schwab M (2018) Clinical pharmacogenetics implementation consortium (CPIC) guideline for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing: 2017 update. Clin Pharmacol Ther 103:210–216PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Schwab M, Zanger UM, Marx C, Schaeffeler E, Klein K, Dippon J, Kerb R, Blievernicht J, Fischer J, Hofmann U, Bokemeyer C, Eichelbaum M, German 5-FU Toxicity Study Group (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 26:2131–2138PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Stein BN, Petrelli NJ, Douglass HO, Driscoll DL, Arcangeli G, Meropol NJ (1995) Age and sex are independent predictors of 5-fluorouracil toxicity. Analysis of a large scale phase III. trial Cancer 75:11–17PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Chansky K, Benedetti J, Macdonald JS (2005) Differences in toxicity between men and women treated with 5-fluorouracil therapy for colorectal carcinoma. Cancer 103:1165–1171PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Zalcberg J, Kerr D, Seymour L, Palmer M (1998) Haematological and non-haematological toxicity after 5-fluorouracil and leucovorin in patients with advanced colorectal cancer is significantly associated with gender, increasing age and cycle number. Tomudex International Study Group. Eur J Cancer 34:1871–1875PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Loganayagam A, Arenas Hernandez M, Corrigan A, Fairbanks L, Lewis CM, Harper P, Maisey N, Ross P, Sanderson JD, Marinaki AM (2013) Pharmacogenetic variants in the DPYD, TYMS, CDA and MTHFR genes are clinically significant predictors of fluoropyrimidine toxicity. Br J Cancer 108:2505–2515PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    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 5:2895–2904PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Terrazzino S, Cargnin S, Del Re M, Danesi R, Canonico PL, Genazzani AA (2013) DPYD IVS14 + 1G> A and 2846A> T genotyping for the prediction of severe fluoropyrimidine-related toxicity: a meta-analysis. Pharmacogenomics 14:1255–1272PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Meulendijks D, Henricks LM, Sonke GS, Deenen MJ, Froehlich TK, Amstutz U, Largiader CR, Jennings BA, Marinaki AM, Sanderson JD, Kleibl Z, Kleiblova P, Schwab M, Zanger UM, Palles C, Tomlinson I, Gross E, van Kuilenburg AB, Punt CJ, Koopman M, Beijnen JH, Cats A, Schellens JH (2015) Clinical relevance of DPYD variants c.1679T> G, c.1236G> A/HapB3, and c.1601G> A as predictors of severe fluoropyrimidine-associated toxicity: a systematic review and meta-analysis of individual patient data. Lancet Oncol 16:1639–1650PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Lee AM, Shi Q, Pavey E, Alberts SR, Sargent DJ, Sinicrope FA, Berenberg JL, Goldberg RM, Diasio RB (2014) DPYD variants as predictors of 5-fluorouracil toxicity in adjuvant colon cancer treatment. J Natl Cancer Inst.  https://doi.org/10.1093/jnci/dju298 CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Yen-Revollo JL, Auman JT, McLeod HL (2008) Race does not explain genetic heterogeneity in pharmacogenomic pathways. Pharmacogenomics 9:1639–1645PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Sanoff HK, Sargent DJ, Green EM, McLeod HL, Goldberg RM (2009) Racial differences in advanced colorectal cancer outcomes and pharmacogenetics: a subgroup analysis of a large randomized clinical trial. J Clin Oncol 27:4109–4115PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    U.S. National Library of Medicine (2017) Label: fluorouracil–fluorouracil injection, solution. U.S. Department of Health and Human Services. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=66d451fe-2436-494c-80c5-4528c8e34369&audience=professional. Accessed 5 May 2018
  67. 67.
    Ehmann F, Caneva L, Papaluca M (2014) European Medicines Agency initiatives and perspectives on pharmacogenomics. Br J Clin Pharmacol 77:612–617PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Rosmarin D, Palles C, Church D, Domingo E, Jones A, Johnstone E, Wang H, Love S, Julier P, Scudder C, Nicholson G, Gonzalez-Neira A, Martin M, Sargent D, Green E, McLeod H, Zanger UM, Schwab M, Braun M, Seymour M, Thompson L, Lacas B, Boige V, Ribelles N, Afzal S, Enghusen H, Jensen SA, Etienne-Grimaldi MC, Milano G, Wadelius M, Glimelius B, Garmo H, Gusella M, Lecomte T, Laurent-Puig P, Martinez-Balibrea E, Sharma R, Garcia-Foncillas J, Kleibl Z, Morel A, Pignon JP, Midgley R, Kerr D, Tomlinson I (2014) Genetic markers of toxicity from capecitabine and other fluorouracil-based regimens: investigation in the QUASAR2 study, systematic review, and meta-analysis. J Clin Oncol 32:1031–1039PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    National Center for Biotechnology Information (2018) dbSNP Short Genetic Variants. U.S. Department of Health and Human Services http://www.ncbi.nlm.nih.gov/SNP/. Accessed 6 May 2018
  70. 70.
    Hunt R, Sauna ZE, Ambudkar SV, Gottesman MM, Kimchi-Sarfaty C (2009) Silent (synonymous) SNPs: should we care about them? Methods Mol Biol 578:23–39PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Song Z, Yao C, Yin J, Tong C, Zhu D, Sun Z, Jiang J, Shao M, Zhang Y, Deng Z, Tao Z, Sun S, Bai C (2012) Genetic variation in the TNF receptor-associated factor 6 gene is associated with susceptibility to sepsis-induced acute lung injury. J Transl Med 10:166–176PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Finco TS, Baldwin AS (1995) Mechanistic aspects of NF-kappa B regulation: the emerging role of phosphorylation and proteolysis. Immunity 3:263–272PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Bogunia-Kubik K, Polak M, Lange A (2003) TNF polymorphisms are associated with toxic but not with aGVHD complications in the recipients of allogeneic sibling haematopoietic stem cell transplantation. Bone Marrow Transpl 32:617–622CrossRefGoogle Scholar
  74. 74.
    Karban AS, Okazaki T, Panhuysen CI, Gallegos T, Potter JJ, Bailey-Wilson JE, Silverberg MS, Duerr RH, Cho JH, Gregersen PK, Wu Y, Achkar JP, Dassopoulos T, Mezey E, Bayless TM, Nouvet FJ, Brant SR (2004) Functional annotation of a novel NFKB1 promoter polymorphism that increases risk for ulcerative colitis. Hum Mol Genet 13:35–45PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Pinero P, Juanola O, Caparros E, Zapater P, Gimenez P, Gonzalez-Navajas JM, Such J, Frances R (2017) Toll-like receptor polymorphisms compromise the inflammatory response against bacterial antigen translocation in cirrhosis. Sci Rep 7:46425PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Ovsyannikova IG, Haralambieva IH, Vierkant RA, Pankratz VS, Jacobson RM, Poland GA (2011) The role of polymorphisms in Toll-like receptors and their associated intracellular signaling genes in measles vaccine immunity. Hum Genet 130:547–561PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Coller JK, White IA, Logan RM, Tuke J, Richards AM, Mead KR, Karapetis CS, Bowen JM (2015) Predictive model for risk of severe gastrointestinal toxicity following chemotherapy using patient immune genetics and type of cancer: a pilot study. Support Care Cancer 23:1233–1236PubMedCrossRefGoogle Scholar
  78. 78.
    Nachtigall I, Tamarkin A, Tafelski S, Weimann A, Rothbart A, Heim S, Wernecke KD, Spies C (2014) Polymorphisms of the toll-like receptor 2 and 4 genes are associated with faster progression and a more severe course of sepsis in critically ill patients. J Int Med Res 42:93–110PubMedCrossRefGoogle Scholar
  79. 79.
    Schnetzke U, Spies-Weisshart B, Yomade O, Fischer M, Rachow T, Schrenk K, Glaser Av, von Lilienfeld-Toal M, Hochhaus A, Scholl S (2015) Polymorphisms of Toll-like receptors (TLR2 and TLR4) are associated with the risk of infectious complications in acute myeloid leukemia. Genes Immun 16:83–88PubMedCrossRefGoogle Scholar
  80. 80.
    Junjie X, Songyao J, Minmin S, Yanyan S, Baiyong S, Xiaxing D, Jiabin J, Xi Z, Hao C (2012) The association between Toll-like receptor 2 single-nucleotide polymorphisms and hepatocellular carcinoma susceptibility. BMC Cancer 12:57PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Arbour NC, Lorenz E, Schutte BC, Zabner J, Kline JN, Jones M, Frees K, Watt JL, Schwartz DA (2000) TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet 25:187–191PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Guo C, Zhang L, Nie L, Zhang N, Xiao D, Ye X, Ou M, Liu Y, Zhang B, Wang M, Lin H, Yang G, Jing C (2016) Association of polymorphisms in the MyD88, IRAK4 and TRAF6 genes and susceptibility to type 2 diabetes mellitus and diabetic nephropathy in a southern Han Chinese population. Mol Cell Endocrinol 429:114–119PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Carrasco-Colom J, Jordan I, Alsina L, Garcia-Garcia JJ, Cambra-Lasaosa FJ, Martin-Mateos MA, Juan M, Munoz-Almagro C (2015) Association of polymorphisms in IRAK1, IRAK4 and MyD88, and severe invasive pneumococcal disease. Pediatr Infect Dis J 34:1008–1013PubMedCrossRefPubMedCentralGoogle Scholar
  84. 84.
    Arcaroli J, Silva E, Maloney JP, He Q, Svetkauskaite D, Murphy JR, Abraham E (2006) Variant IRAK-1 haplotype is associated with increased nuclear factor-kappaB activation and worse outcomes in sepsis. Am J Respir Crit Care Med 173:1335–1341PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Li C, Huang S, Mo S, Zhang N, Zhou L, Mao Z, Lv W, Li J, Zhou Y (2015) Susceptibility of autoimmune diseases in three polymorphisms of infection-associated gene IRAK1. J Infect Dev Ctries 9:614–623PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Fang Y, Zhang L, Zhou GQ, Wang ZF, Feng K, Lou ZY, Pang W, Li L, Ling Y, Li YX, Liu BC (2010) TRAF6 polymorphisms not associated with the susceptibility to and severity of sepsis in a Chinese population. World J Emerg Med 1:169–175PubMedPubMedCentralGoogle Scholar
  87. 87.
    Andersen V, Christensen J, Ernst A, Jacobsen BA, Tjonneland A, Krarup HB, Vogel U (2011) Polymorphisms in NF-kappaB, PXR, LXR, PPARgamma and risk of inflammatory bowel disease. World J Gastroenterol 17:197–206PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Dzhugashvili M, Luengo-Gil G, Garcia T, Gonzalez-Conejero R, Conesa-Zamora P, Escolar PP, Calvo F, Vicente V, Ayala de la Pena F (2014) Role of genetic polymorphisms in NFKB-mediated inflammatory pathways in response to primary chemoradiation therapy for rectal cancer. Int J Radiat Oncol Biol Phys 90:595–602PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Lacruz-Guzman D, Torres-Moreno D, Pedrero F, Romero-Cara P, Garcia-Tercero I, Trujillo-Santos J, Conesa-Zamora P (2013) Influence of polymorphisms and TNF and IL1beta serum concentration on the infliximab response in Crohn’s disease and ulcerative colitis. Eur J Clin Pharmacol 69:431–438PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Chen H, Wilkins LM, Aziz N, Cannings C, Wyllie DH, Bingle C, Rogus J, Beck JD, Offenbacher S, Cork MJ, Rafie-Kolpin M, Hsieh CM, Kornman KS, Duff GW (2006) Single nucleotide polymorphisms in the human interleukin-1B gene affect transcription according to haplotype context. Hum Mol Genet 15:519–529PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    El-Omar EM, Carrington M, Chow W-H, McColl KE, Bream JH, Young HA, Herrera J, Lissowska J, Yuan C-C, Rothman N (2000) Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature 404:398–402PubMedCrossRefPubMedCentralGoogle Scholar
  92. 92.
    Sakamoto K, Oka M, Yoshino S, Hazama S, Abe T, Okayama N, Hinoda Y (2006) Relation between cytokine promoter gene polymorphism and toxicity of 5-fluorouracil plus cisplatin chemotherapy. Oncol Rep 16:381–387PubMedPubMedCentralGoogle Scholar
  93. 93.
    Brinkman B, Zuijdeest D, Kaijzel EL, Breedveld FC, Verweij CL (1994) Relevance of the tumor necrosis factor alpha (TNF alpha)-308 promoter polymorphism in TNF alpha gene regulation. J Inflamm Res 46:32–41Google Scholar
  94. 94.
    Kroeger KM, Carville KS, Abraham LJ (1997) The—308 tumor necrosis factor-α promoter polymorphism effects transcription. Mol Immunol 34:391–399PubMedCrossRefPubMedCentralGoogle Scholar
  95. 95.
    de Jong BA, Westendorp RG, Bakker AM, Huizinga TW (2002) Polymorphisms in or near tumour necrosis factor (TNF)-gene do not determine levels of endotoxin-induced TNF production. Genes Immun 3:25–29PubMedCrossRefPubMedCentralGoogle Scholar
  96. 96.
    Huizinga TW, Westendorp RG, Bollen EL, Keijsers V, Brinkman BM, Langermans JA, Breedveld FC, Verweij CL, van de Gaer L, Dams L, Crusius JB, Garcia-Gonzalez A, van Oosten BW, Polman CH, Pena AS (1997) TNF-alpha promoter polymorphisms, production and susceptibility to multiple sclerosis in different groups of patients. J Neuroimmunol 72:149–153PubMedCrossRefPubMedCentralGoogle Scholar
  97. 97.
    Yamamoto T, Tsutsumi N, Tochio H, Ohnishi H, Kubota K, Kato Z, Shirakawa M, Kondo N (2014) Functional assessment of the mutational effects of human IRAK4 and MyD88 genes. Mol Immunol 58:66–76PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Cancer Treatment Toxicities Group, Adelaide Medical School, Disciplines of Pharmacology and PhysiologyUniversity of AdelaideAdelaideAustralia
  2. 2.Division of Health SciencesUniversity of South AustraliaAdelaideAustralia

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