title: A Stepwise Integrated Approach to Personalized Risk Predictions in Stage III Colorectal Cancer.
abstract: Purpose:Apoptosis is essential for chemotherapy responses. In this discovery and validation study, we evaluated the suitability of a mathematical model of apoptosis execution (APOPTO-CELL) as a stand-alone signature and as a constituent of further refined prognostic stratification tools.Experimental Design:Apoptosis competency of primary tumor samples from patients with stage III colorectal cancer (n= 120) was calculated by APOPTO-CELL from measured protein concentrations of Procaspase-3, Procaspase-9, SMAC, and XIAP. An enriched APOPTO-CELL signature (APOPTO-CELL-PC3) was synthesized to capture apoptosome-independent effects of Caspase-3. Furthermore, a machine learning Random Forest approach was applied to APOPTO-CELL-PC3 and available molecular and clinicopathologic data to identify a further enhanced signature. Association of the signature with prognosis was evaluated in an independent colon adenocarcinoma cohort (TCGA COAD,n= 136).Results:We identified 3 prognostic biomarkers (P= 0.04,P= 0.006, andP= 0.0004 for APOPTO-CELL, APOPTO-CELL-PC3, and Random Forest signatures, respectively) with increasing stratification accuracy for patients with stage III colorectal cancer.The APOPTO-CELL-PC3 signature ranked highest among all features. The prognostic value of the signatures was independently validated in stage III TCGA COAD patients (P= 0.01,P= 0.04, andP= 0.02 for APOPTO-CELL, APOPTO-CELL-PC3, and Random Forest signatures, respectively). The signatures provided further stratification for patients with CMS1-3 molecular subtype.Conclusions:The integration of a systems-biology-based biomarker for apoptosis competency with machine learning approaches is an appealing and innovative strategy toward refined patient stratification. The prognostic value of apoptosis competency is independent of other available clinicopathologic and molecular factors, with tangible potential of being introduced in the clinical management of patients with stage III colorectal cancer.Clin Cancer Res; 23(5); 1200-12. ©2016 AACR.
authors.affiliation: Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.|Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
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authors.lastname: Salvucci
authors.affiliation: Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.|Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Maximilian L
authors.initials: ML
authors.lastname: Würstle
authors.affiliation: Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.|Department of Medical Oncology, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Clare
authors.initials: C
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authors.affiliation: Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.|Department of Pathology, Beaumont Hospital, Dublin, Ireland.
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authors.affiliation: Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.|Department of Medical Oncology, Royal College of Surgeons in Ireland, Dublin, Ireland.
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authors.affiliation: Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.|Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Andreas U
authors.initials: AU
authors.lastname: Lindner
authors.affiliation: Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.|Department of Surgery, Beaumont Hospital, Dublin, Ireland.
authors.forename: Orna
authors.initials: O
authors.lastname: Bacon
authors.affiliation: Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.|Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Alexa J
authors.initials: AJ
authors.lastname: Resler
authors.affiliation: Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.|Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Áine C
authors.initials: ÁC
authors.lastname: Murphy
authors.affiliation: Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.|Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Robert
authors.initials: R
authors.lastname: O'Byrne
authors.affiliation: Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.|Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Lorna
authors.initials: L
authors.lastname: Flanagan
authors.affiliation: Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, United Kingdom.
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authors.lastname: Dasgupta
authors.affiliation: Faculté de Médecine, Université Paris Descartes, Paris, France.
authors.forename: Nadege
authors.initials: N
authors.lastname: Rice
authors.affiliation: INSERM UMR-S1147, Personalized Medicine, Pharmacogenomics, Therapeutic Optimization, Université Paris Descartes, Paris, France.
authors.forename: Camilla
authors.initials: C
authors.lastname: Pilati
authors.affiliation: Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.|Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Zink
authors.affiliation: Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.|Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Schöller
authors.affiliation: Department of Medical Oncology, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Sinead
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authors.lastname: Toomey
authors.affiliation: Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, United Kingdom.
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authors.lastname: Lawler
authors.affiliation: Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, United Kingdom.
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authors.initials: PG
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authors.affiliation: Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Wilson
authors.affiliation: Department of Pathology, Université Paris Descartes, Paris, France.
authors.forename: Sophie
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authors.affiliation: Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, United Kingdom.
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authors.affiliation: Department of Surgery, Beaumont Hospital, Dublin, Ireland.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: McNamara
authors.affiliation: Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.|Department of Pathology, Beaumont Hospital, Dublin, Ireland.
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authors.initials: EW
authors.lastname: Kay
authors.affiliation: INSERM UMR-S1147, Personalized Medicine, Pharmacogenomics, Therapeutic Optimization, Université Paris Descartes, Paris, France.
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authors.initials: P
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authors.affiliation: Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, United Kingdom.
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authors.initials: S
authors.lastname: Van Schaeybroeck
authors.affiliation: Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.|Department of Medical Oncology, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Bryan T
authors.initials: BT
authors.lastname: Hennessy
authors.affiliation: Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, United Kingdom.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Longley
authors.affiliation: Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.|Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.|Institute of Cell Biology and Immunology, University of Stuttgart, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Rehm
authors.affiliation: Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland. prehn@rcsi.ie.|Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Jochen H M
authors.initials: JH
authors.lastname: Prehn
mesh_terms: D000368:Aged; D017209:Apoptosis / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics*; D053148:Caspase 3 / Q000235:genetics; D053453:Caspase 9 / Q000235:genetics; D015179:Colorectal Neoplasms / Q000453:epidemiology* / Q000235:genetics* / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D000069550:Machine Learning; D008297:Male; D008875:Middle Aged; D008962:Models, Theoretical; D009367:Neoplasm Staging; D057285:Precision Medicine; D011379:Prognosis; D018570:Risk Assessment; D049490:Systems Biology
chemical_list: D014408:Biomarkers, Tumor; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9