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BCL-2 system analysis identifies high-risk colorectal cancer patients
- Source :
- Gut. 66:2141-2148
- Publication Year :
- 2016
- Publisher :
- BMJ, 2016.
-
Abstract
- ObjectiveThe 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).DesignAbsolute 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.ResultsHigh-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.ConclusionsDR_MOMP delivers a system-based biomarker with significant potential as a prognostic tool for stage III CRC that significantly improves established histopathological risk factors.
- Subjects :
- Adult
Male
0301 basic medicine
Oncology
medicine.medical_specialty
Lymphovascular invasion
Colorectal cancer
Apoptosis
Bioinformatics
Risk Assessment
03 medical and health sciences
0302 clinical medicine
Cancer genome
Internal medicine
Gene expression
Biomarkers, Tumor
medicine
Humans
In patient
Pathological
Neoplasm Staging
business.industry
Gastroenterology
Decision Support Systems, Clinical
Prognosis
medicine.disease
3. Good health
Survival Rate
030104 developmental biology
Proto-Oncogene Proteins c-bcl-2
Lymphatic Metastasis
030220 oncology & carcinogenesis
Cohort
Female
Colorectal Neoplasms
business
Subjects
Details
- ISSN :
- 14683288 and 00175749
- Volume :
- 66
- Database :
- OpenAIRE
- Journal :
- Gut
- Accession number :
- edsair.doi.dedup.....c09a69902bf0dc0c4b0a432e540fa684