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Systems biology analysis identifies molecular determinants of chemotherapy-induced diarrhoea

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Abstract

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.

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Abbreviations

a.U.:

arbitrary unit

BAK:

BCL2 antagonist/killer 1 (BAK1)

BAX:

BCL2 associated X, apoptosis regulator (BCL2L4)

BCL2:

B cell lymphoma 2

BCL(X)L:

B cell lymphoma-extra large (BCL2L1)

CED:

cycle with episodes of diarrhoea

CI:

confidence interval

CID:

chemotherapy-induced diarrhoea

MCL1:

Myeloid cell leukaemia sequence 1 (BCL2L3)

MLR:

multinomial logistic regression

MOMP:

mitochondrial outer membrane permeabilisation

nM:

nanomolar (10^–9 mol/L)

RPPA:

reverse protein phase array

TNM:

tumour/lymph node/metastasis staging system

Tukey HSD:

Tukey honest significant differences post hoc test

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Authors and Affiliations

  1. Centre for Systems Medicine and Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen’s Green, Dublin 2, Ireland

    Andreas U. Lindner, Alexa J. Resler, Steven Carberry, Orna Bacon, Abdurehman Choudhry & Jochen H.M. Prehn

  2. Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland

    Andreas U. Lindner, Alexa J. Resler, Steven Carberry, Orna Bacon, Abdurehman Choudhry & Jochen H.M. Prehn

  3. Centre for Colorectal Disease, St. Vincent’s University Hospital, Elm Park, Dublin, Ireland

    Kasia Oficjalska, Chun Seng Lee, Kieran Sheahan, Glen Doherty & Elizabeth J. Ryan

  4. Department of Surgery, Beaumont Hospital, Dublin 9, Ireland

    Orna Bacon, John P. Burke & Deborah McNamara

  5. Department of Pathology, St. Vincent’s University Hospital, Elm Park, Dublin, Ireland

    Kieran Sheahan

  6. Department of Medical Oncology, Beaumont Hospital, Dublin 9, Ireland

    Mattia Cremona & Bryan T Hennessy

  7. School of Medicine & Medical Science, University College Dublin, Dublin, Ireland

    Glen Doherty & Elizabeth J. Ryan

  8. Health Research Institute, University of Limerick, Limerick, Ireland

    Elizabeth J. Ryan

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  1. Andreas U. Lindner
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  2. Alexa J. Resler
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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.

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Correspondence to Jochen H.M. Prehn.

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Lindner, A.U., Resler, A.J., Carberry, S. et al. Systems biology analysis identifies molecular determinants of chemotherapy-induced diarrhoea. J Mol Med 98, 149–159 (2020). https://doi.org/10.1007/s00109-019-01864-z

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