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 journalArticlepeer-review

25 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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