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



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.


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.


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.


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.


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





Damage associated molecular patterns


Dihydropyrimidine dehydrogenase enzyme


Dihydropyrimidine dehydrogenase gene




Hematopoietic stem cell transplantation


Inhibitor of NF-κB-kinase complex


Interleukin-1 receptor-associated kinases 1


Interleukin-1 receptor-associated kinases 4


Myeloid differentiation primary response protein 88


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


Pathogen associated molecular patterns


Peripheral blood mononuclear cells


Single nucleotide polymorphisms


Tak-1 binding protein 1


Tak-1 binding protein 2


Transforming growth factor beta factor-β activated kinase 1


Toll-like receptor/interleukin-1


Toll-like receptor


TNF receptor associated factor 6



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.


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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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