Systems biology analysis identifies molecular determinants of chemotherapy-induced diarrhoea. Merged files.pdf (8.87 MB)
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Systems biology analysis identifies molecular determinants of chemotherapy-induced diarrhoea

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posted on 07.12.2021, 11:46 by Andreas Ulrich LindnerAndreas Ulrich Lindner, Alex J Resler, Steven Carberry, Kasia Oficjalska, Orna Bacon, Chun Seng Lee, Abdurehman ChoudhryAbdurehman Choudhry, John BurkeJohn Burke, Kieran Sheahan, Mattia CremonaMattia Cremona, Bryan HennessyBryan Hennessy, Deborah McNamaraDeborah McNamara, Glen Doherty, Elizabeth J Ryan, Jochen PrehnJochen Prehn
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.

Funding

Investigator Award from Science Foundation Ireland (13/IA/ 1881)

History

Comments

The original article is available at https://link.springer.com

Published Citation

Lindner AU. et al. Systems biology analysis identifies molecular determinants of chemotherapy-induced diarrhoea. J Mol Med (Berl). 2020;98(1):149-159.

Publication Date

17 December 2019

PubMed ID

31848663

Department/Unit

  • Beaumont Hospital
  • Centre for Systems Medicine
  • Molecular Medicine
  • Physiology and Medical Physics

Research Area

  • Cancer
  • Neurological and Psychiatric Disorders

Publisher

Springer Science and Business Media LLC

Version

  • Accepted Version (Postprint)