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

Andreas U Lindner, Manuela Salvucci, C Morgan, N Monsefi, AJ Resler, M Cremona, S Curry, S Toomey, Robert O'Byrne, Orna Bacon, M Stuhler, Lorna Flanagan, Richard Wilson, P.G. Johnston, Manuel Salto-Tellez, Sophie Camilleri-Broët, Deborah A McNamara, Elaine Kay, Bryan T Hennessy, P Laurent-PuigSandra Van Schaeybroeck, Jochen H M Prehn

Research output: Contribution to journalArticle

20 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)2141-2148
JournalGut
Volume66
Issue number12
Early online date23 Sep 2016
DOIs
Publication statusPublished - 13 Nov 2017

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  • Cite this

    Lindner, A. U., Salvucci, M., Morgan, C., Monsefi, N., Resler, AJ., Cremona, M., Curry, S., Toomey, S., O'Byrne, R., Bacon, O., Stuhler, M., Flanagan, L., Wilson, R., Johnston, P. G., Salto-Tellez, M., Camilleri-Broët, S., McNamara, D. A., Kay, E., Hennessy, B. T., ... Prehn, J. H. M. (2017). BCL-2 system analysis identifies high-risk colorectal cancer patients. Gut, 66(12), 2141-2148. https://doi.org/10.1136/gutjnl-2016-312287