Journal of Molecular Medicine

, Volume 98, Issue 1, pp 149–159 | Cite as

Systems biology analysis identifies molecular determinants of chemotherapy-induced diarrhoea

  • Andreas U. Lindner
  • Alexa J. Resler
  • Steven Carberry
  • Kasia Oficjalska
  • Orna Bacon
  • Chun Seng Lee
  • Abdurehman Choudhry
  • John P. Burke
  • Kieran Sheahan
  • Mattia Cremona
  • Bryan T Hennessy
  • Deborah McNamara
  • Glen Doherty
  • Elizabeth J. Ryan
  • Jochen H.M. PrehnEmail author
Original Article


Chemotherapy-induced diarrhoea (CID) is a common dose-limiting adverse event in patients with cancer. Here, we hypothesise that chemotherapy evokes apoptosis in normal gut epithelium, contributes to CID and that patients with increased risk of CID can be identified using a systems model of BCL-2 protein interactions (DR_MOMP) that calculates the sensitivity of cells to undergo apoptosis. Normal adjacent gut epithelium tissue was collected during resection surgery from a cohort of 35 patients with stage II–III colorectal cancer (CRC) who were subsequently treated with capecitabine, XELOX or FOLFOX. Clinical follow-up, type and grade of adverse events during adjuvant chemotherapy were recorded. The level of five BCL-2 proteins required for the calculation of the DR_MOMP score was quantified together with 62 additional signalling proteins related to apoptotic pathways. Odds ratios for the occurrence of diarrhoea were determined using multinomial logistic regression (MLR). Patients treated with capecitabine who had a DR_MOMP score equal or higher than the mean had a significantly lower frequency of diarrhoea significantly compared to patients below the mean. High DR_MOMP scores indicate high apoptosis resistance. No statistical difference was observed in patients treated with XELOX or FOLFOX. Using MLR, we found that levels of apoptosis-related proteins caspase-8, p53 and XIAP statistically interacted with the DR_MOMP stress dose. Markers of MAPK signalling were prognostic for diarrhoea independently of DR_MOMP. In conclusion, apoptosis sensitivity and MAPK signalling status of the adjacent normal gut epithelium of chemotherapy-naïve patients represent promising biomarkers to identify patients with CRC with increased risk of CID.


BCL-2 Systems biology Adverse effect Apoptosis Colorectal Cancer 



arbitrary unit


BCL2 antagonist/killer 1 (BAK1)


BCL2 associated X, apoptosis regulator (BCL2L4)


B cell lymphoma 2


B cell lymphoma-extra large (BCL2L1)


cycle with episodes of diarrhoea


confidence interval


chemotherapy-induced diarrhoea


Myeloid cell leukaemia sequence 1 (BCL2L3)


multinomial logistic regression


mitochondrial outer membrane permeabilisation


nanomolar (10^–9 mol/L)


reverse protein phase array


tumour/lymph node/metastasis staging system

Tukey HSD

Tukey honest significant differences post hoc test


Authors’ contributions

AUL and JHMP wrote the manuscript and prepared figures. AUL and AJR conducted the computational and statistical analysis. CSL, KO, OB, AC, JPB, DMN, KS and GD performed acquisition and processing of data. SC conducted protein quantification. DMN, GD, ER and JHMP supervised the project. All authors read, reviewed and approved the final manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Andreas U. Lindner
    • 1
    • 2
  • Alexa J. Resler
    • 1
    • 2
  • Steven Carberry
    • 1
    • 2
  • Kasia Oficjalska
    • 3
  • Orna Bacon
    • 1
    • 2
    • 4
  • Chun Seng Lee
    • 3
  • Abdurehman Choudhry
    • 1
    • 2
  • John P. Burke
    • 4
  • Kieran Sheahan
    • 3
    • 5
  • Mattia Cremona
    • 6
  • Bryan T Hennessy
    • 6
  • Deborah McNamara
    • 4
  • Glen Doherty
    • 3
    • 7
  • Elizabeth J. Ryan
    • 3
    • 7
    • 8
  • Jochen H.M. Prehn
    • 1
    • 2
    Email author
  1. 1.Centre for Systems Medicine and Department of Physiology and Medical PhysicsRoyal College of Surgeons in IrelandDublin 2Ireland
  2. 2.Department of Physiology and Medical PhysicsRoyal College of Surgeons in IrelandDublin 2Ireland
  3. 3.Centre for Colorectal DiseaseSt. Vincent’s University HospitalDublinIreland
  4. 4.Department of SurgeryBeaumont HospitalDublin 9Ireland
  5. 5.Department of PathologySt. Vincent’s University HospitalDublinIreland
  6. 6.Department of Medical OncologyBeaumont HospitalDublin 9Ireland
  7. 7.School of Medicine & Medical ScienceUniversity College DublinDublinIreland
  8. 8.Health Research InstituteUniversity of LimerickLimerickIreland

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