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



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.



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.



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.
Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.|Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
Andreas U
AU
Lindner
Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.|Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
Manuela
M
Salvucci
Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.|Departments of Molecular Medicine and Oncology, Royal College of Surgeons in Ireland, Dublin, Ireland.
Clare
C
Morgan
Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.|Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
Naser
N
Monsefi
Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.|Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
Alexa J
AJ
Resler
Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.|Departments of Molecular Medicine and Oncology, Royal College of Surgeons in Ireland, Dublin, Ireland.
Mattia
M
Cremona
Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.|Departments of Pathology, Royal College of Surgeons in Ireland, Dublin, Ireland.
Sarah
S
Curry
Departments of Molecular Medicine and Oncology, Royal College of Surgeons in Ireland, Dublin, Ireland.
Sinead
S
Toomey
Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.|Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
Robert
R
O'Byrne
Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.|Departments of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland.
Orna
O
Bacon
Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.|Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
Michael
M
Stühler
Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.|Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
Lorna
L
Flanagan
Centre for Cancer Research and Cell Biology, School of Medicine, Queen's University Belfast, Belfast, UK.
Richard
R
Wilson
Centre for Cancer Research and Cell Biology, School of Medicine, Queen's University Belfast, Belfast, UK.
Patrick G
PG
Johnston
Centre for Cancer Research and Cell Biology, School of Medicine, Queen's University Belfast, Belfast, UK.
Manuel
M
Salto-Tellez
Department of Pathology, Université Paris Descartes, UMR-S 1147, Paris, France.
Sophie
S
Camilleri-Broët
Departments of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland.
Deborah A
DA
McNamara
Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.|Departments of Pathology, Royal College of Surgeons in Ireland, Dublin, Ireland.
Elaine W
EW
Kay
Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.|Departments of Molecular Medicine and Oncology, Royal College of Surgeons in Ireland, Dublin, Ireland.
Bryan T
BT
Hennessy
UMR-S 1147, Université Paris Descartes, Paris, France, France.
Pierre
P
Laurent-Puig
Centre for Cancer Research and Cell Biology, School of Medicine, Queen's University Belfast, Belfast, UK.
Sandra
S
Van Schaeybroeck
Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.|Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
Jochen H M
JHM
Prehn
D000328:Adult; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D020000:Decision Support Systems, Clinical; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D009367:Neoplasm Staging; D011379:Prognosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D018570:Risk Assessment; D015996:Survival Rate
D014408:Biomarkers, Tumor; D019253:Proto-Oncogene Proteins c-bcl-2
ADJUVANT TREATMENT; APOPTOSIS; BCL-2 FAMILY PROTEINS; CLINICAL DECISION MAKING; COLORECTAL CANCER