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Original article
BCL-2 system analysis identifies high-risk colorectal cancer patients
  1. Andreas U Lindner1,2,
  2. Manuela Salvucci1,2,
  3. Clare Morgan1,3,
  4. Naser Monsefi1,2,
  5. Alexa J Resler1,2,
  6. Mattia Cremona1,3,
  7. Sarah Curry1,4,
  8. Sinead Toomey3,
  9. Robert O'Byrne1,2,
  10. Orna Bacon2,5,
  11. Michael Stühler1,2,
  12. Lorna Flanagan1,2,
  13. Richard Wilson6,
  14. Patrick G Johnston6,
  15. Manuel Salto-Tellez6,
  16. Sophie Camilleri-Broët7,
  17. Deborah A McNamara5,
  18. Elaine W Kay1,4,
  19. Bryan T Hennessy1,3,
  20. Pierre Laurent-Puig8,
  21. Sandra Van Schaeybroeck6,
  22. Jochen H M Prehn1,2
  1. 1Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
  2. 2Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
  3. 3Departments of Molecular Medicine and Oncology, Royal College of Surgeons in Ireland, Dublin, Ireland
  4. 4Departments of Pathology, Royal College of Surgeons in Ireland, Dublin, Ireland
  5. 5Departments of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland
  6. 6Centre for Cancer Research and Cell Biology, School of Medicine, Queen's University Belfast, Belfast, UK
  7. 7Department of Pathology, Université Paris Descartes, UMR-S 1147, Paris, France
  8. 8UMR-S 1147, Université Paris Descartes, Paris, France, France
  1. Correspondence to Professor Jochen H M Prehn, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland; prehn{at}rcsi.ie

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.

  • APOPTOSIS
  • BCL-2 FAMILY PROTEINS
  • COLORECTAL CANCER
  • CLINICAL DECISION MAKING
  • ADJUVANT TREATMENT

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