Systems biology analysis identifies molecular determinants of chemotherapy-induced diarrhoea
journal contributionposted on 2021-12-07, 11:46 authored by Andreas Ulrich Lindner, Alex J Resler, Steven Carberry, Kasia Oficjalska, Orna Bacon, Chun Seng Lee, Abdurehman ChoudhryAbdurehman Choudhry, John BurkeJohn Burke, Kieran Sheahan, Mattia 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.
Investigator Award from Science Foundation Ireland (13/IA/ 1881)
CommentsThe original article is available at https://link.springer.com
Published CitationLindner AU. et al. Systems biology analysis identifies molecular determinants of chemotherapy-induced diarrhoea. J Mol Med (Berl). 2020;98(1):149-159.
Publication Date17 December 2019
- Beaumont Hospital
- Centre for Systems Medicine
- Molecular Medicine
- Physiology and Medical Physics
- Neurological and Psychiatric Disorders
PublisherSpringer Science and Business Media LLC
- Accepted Version (Postprint)
Adverse effectApoptosisBCL-2CancerColorectalSystems biologyAntimetabolites, AntineoplasticAntineoplastic Combined Chemotherapy ProtocolsBiomarkers, TumorCapecitabineChemotherapy, AdjuvantColorectal NeoplasmsDiarrheaFluorouracilFollow-Up StudiesIntestinal MucosaLeucovorinMitogen-Activated Protein KinasesOrganoplatinum CompoundsOxaloacetatesPrognosisProto-Oncogene Proteins c-bcl-2Systems BiologyImmunologyMedicinal and Biomolecular Chemistry