OBJECTIVE: The mitochondrial apoptosis pathway is controlled by an interaction of multiple BCL-2 family proteins, and plays a key role in tumour progression and therapy responses. We assessed the prognostic potential of an experimentally validated, mathematical model of BCL-2 protein interactions (DR_MOMP) in patients with stage III colorectal cancer (CRC). DESIGN: Absolute protein levels of BCL-2 family proteins were determined in primary CRC tumours collected from n=128 resected and chemotherapy-treated patients with stage III CRC. We applied DR_MOMP to categorise patients as high or low risk based on model outputs, and compared model outputs with known prognostic factors (T-stage, N-stage, lymphovascular invasion). DR_MOMP signatures were validated on protein of n=156 patients with CRC from the Cancer Genome Atlas (TCGA) project. RESULTS: High-risk stage III patients identified by DR_MOMP had an approximately fivefold increased risk of death compared with patients identified as low risk (HR 5.2, 95% CI 1.4 to 17.9, p=0.02). The DR_MOMP signature ranked highest among all molecular and pathological features analysed. The prognostic signature was validated in the TCGA colon adenocarcinoma (COAD) cohort (HR 4.2, 95% CI 1.1 to 15.6, p=0.04). DR_MOMP also further stratified patients identified by supervised gene expression risk scores into low-risk and high-risk categories. BCL-2-dependent signalling critically contributed to treatment responses in consensus molecular subtypes 1 and 3, linking for the first time specific molecular subtypes to apoptosis signalling. CONCLUSIONS: DR_MOMP delivers a system-based biomarker with significant potential as a prognostic tool for stage III CRC that significantly improves established histopathological risk factors. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
OBJECTIVE: The mitochondrial apoptosis pathway is controlled by an interaction of multiple BCL-2 family proteins, and plays a key role in tumour progression and therapy responses. We assessed the prognostic potential of an experimentally validated, mathematical model of BCL-2 protein interactions (DR_MOMP) in patients with stage III colorectal cancer (CRC). DESIGN: Absolute protein levels of BCL-2 family proteins were determined in primary CRC tumours collected from n=128 resected and chemotherapy-treated patients with stage III CRC. We applied DR_MOMP to categorise patients as high or low risk based on model outputs, and compared model outputs with known prognostic factors (T-stage, N-stage, lymphovascular invasion). DR_MOMP signatures were validated on protein of n=156 patients with CRC from the Cancer Genome Atlas (TCGA) project. RESULTS: High-risk stage III patients identified by DR_MOMP had an approximately fivefold increased risk of death compared with patients identified as low risk (HR 5.2, 95% CI 1.4 to 17.9, p=0.02). The DR_MOMP signature ranked highest among all molecular and pathological features analysed. The prognostic signature was validated in the TCGA colon adenocarcinoma (COAD) cohort (HR 4.2, 95% CI 1.1 to 15.6, p=0.04). DR_MOMP also further stratified patients identified by supervised gene expression risk scores into low-risk and high-risk categories. BCL-2-dependent signalling critically contributed to treatment responses in consensus molecular subtypes 1 and 3, linking for the first time specific molecular subtypes to apoptosis signalling. CONCLUSIONS: DR_MOMP delivers a system-based biomarker with significant potential as a prognostic tool for stage III CRC that significantly improves established histopathological risk factors. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
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Keywords:
ADJUVANT TREATMENT; APOPTOSIS; BCL-2 FAMILY PROTEINS; CLINICAL DECISION MAKING; COLORECTAL CANCER
Authors: Andreas U Lindner; Federico Lucantoni; Damir Varešlija; Alexa Resler; Brona M Murphy; William M Gallagher; Arnold D K Hill; Leonie S Young; Jochen H M Prehn Journal: J Mol Med (Berl) Date: 2018-08-01 Impact factor: 4.599
Authors: 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 Prehn Journal: J Mol Med (Berl) Date: 2019-12-17 Impact factor: 4.599
Authors: Federico Lucantoni; Andreas U Lindner; Norma O'Donovan; Heiko Düssmann; Jochen H M Prehn Journal: Cell Death Dis Date: 2018-01-19 Impact factor: 8.469
Authors: Philip D Dunne; Helen G Coleman; Peter Bankhead; Matthew Alderdice; Ronan T Gray; Stephen McQuaid; Victoria Bingham; Maurice B Loughrey; Jacqueline A James; Amy M B McCorry; Alan Gilmore; Caitriona Holohan; Dirk Klingbiel; Sabine Tejpar; Patrick G Johnston; Darragh G McArt; Federica Di Nicolantonio; Daniel B Longley; Mark Lawler Journal: Oncotarget Date: 2018-02-13