BCL-2 system analysis identifies high-risk colorectal cancer patients

Lindner, A. U. et al. (2017) BCL-2 system analysis identifies high-risk colorectal cancer patients. Gut, 66(12), pp. 2141-2148. (doi: 10.1136/gutjnl-2016-312287) (PMID:27663504)

Abstract

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.

• Item Type: Articles
• Additional Information: This work has received funding from a Science Foundation Ireland Investigator Award to JHMP (13/IA/1881) and the European Union’s Seventh Framework Programme (FP7 APO-DECIDE) under contract No. 306021.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Wilson, Professor Richard
• Authors: Lindner, A. U., Salvucci, M., Morgan, C., Monsefi, N., Resler, A. J., Cremona, M., Curry, S., Toomey, S., O'Byrne, R., Bacon, O., Stühler, M., Flanagan, L., Wilson, R., Johnston, P. G., Salto-Tellez, M., Camilleri-Broët, S., McNamara, D. A., Kay, E. W., Hennessy, B. T., Laurent-Puig, P., Van Schaeybroeck, S., and Prehn, J. H.M.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Gut
• Publisher: BMJ Publishing Group
• ISSN: 0017-5749
• ISSN (Online): 1468-3288
• Published Online: 23 September 2016