PT  - JOURNAL ARTICLE
AU  - Andreas U Lindner
AU  - Manuela Salvucci
AU  - Clare Morgan
AU  - Naser Monsefi
AU  - Alexa J Resler
AU  - Mattia Cremona
AU  - Sarah Curry
AU  - Sinead Toomey
AU  - Robert O'Byrne
AU  - Orna Bacon
AU  - Michael Stühler
AU  - Lorna Flanagan
AU  - Richard Wilson
AU  - Patrick G Johnston
AU  - Manuel Salto-Tellez
AU  - Sophie Camilleri-Broët
AU  - Deborah A McNamara
AU  - Elaine W Kay
AU  - Bryan T Hennessy
AU  - Pierre Laurent-Puig
AU  - Sandra Van Schaeybroeck
AU  - Jochen H M Prehn
TI  - BCL-2 system analysis identifies high-risk colorectal cancer patients
AID  - 10.1136/gutjnl-2016-312287
DP  - 2017 Dec 01
TA  - Gut
PG  - 2141--2148
VI  - 66
IP  - 12
4099  - http://gut.bmj.com/content/66/12/2141.short
4100  - http://gut.bmj.com/content/66/12/2141.full
SO  - Gut2017 Dec 01; 66
AB  - 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.