title: Wild-type APC predicts poor prognosis in microsatellite-stable proximal colon cancer.
abstract: BACKGROUND
  APC mutations (APC-mt) occur in ∼70% of colorectal cancers (CRCs), but their relationship to prognosis is unclear.
  
  
  METHODS
  APC prognostic value was evaluated in 746 stage I-IV CRC patients, stratifying for tumour location and microsatellite instability (MSI). Microarrays were used to identify a gene signature that could classify APC mutation status, and classifier ability to predict prognosis was examined in an independent cohort.
  
  
  RESULTS
  Wild-type APC microsatellite stable (APC-wt/MSS) tumours from the proximal colon showed poorer overall and recurrence-free survival (OS, RFS) than APC-mt/MSS proximal, APC-wt/MSS distal and APC-mt/MSS distal tumours (OS HR⩾1.79, P⩽0.015; RFS HR⩾1.88, P⩽0.026). APC was a stronger prognostic indicator than BRAF, KRAS, PIK3CA, TP53, CpG island methylator phenotype or chromosomal instability status (P⩽0.036). Microarray analysis similarly revealed poorer survival in MSS proximal cancers with an APC-wt-like signature (P=0.019). APC status did not affect outcomes in MSI tumours. In a validation on 206 patients with proximal colon cancer, APC-wt-like signature MSS cases showed poorer survival than APC-mt-like signature MSS or MSI cases (OS HR⩾2.50, P⩽0.010; RFS HR⩾2.14, P⩽0.025). Poor prognosis APC-wt/MSS proximal tumours exhibited features of the sessile serrated neoplasia pathway (P⩽0.016).
  
  
  CONCLUSIONS
  APC-wt status is a marker of poor prognosis in MSS proximal colon cancer.
authors: Systems Biology and Personalised Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.|Faculty of Medicine, Dentistry and Health Sciences, Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.
authors: Robert N
authors: RN
authors: Jorissen
authors: Systems Biology and Personalised Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.|Faculty of Medicine, Dentistry and Health Sciences, Department of Surgery, University of Melbourne, Parkville, VIC 3010, Australia.
authors: Michael
authors: M
authors: Christie
authors: Systems Biology and Personalised Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.|Faculty of Medicine, Dentistry and Health Sciences, Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.
authors: Dmitri
authors: D
authors: Mouradov
authors: Systems Biology and Personalised Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.|Faculty of Medicine, Dentistry and Health Sciences, Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.
authors: Anuratha
authors: A
authors: Sakthianandeswaren
authors: Systems Biology and Personalised Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
authors: Shan
authors: S
authors: Li
authors: Systems Biology and Personalised Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.|Faculty of Medicine, Dentistry and Health Sciences, Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.
authors: Christopher
authors: C
authors: Love
authors: CSIRO Preventative Health Flagship, Animal, Food & Health Sciences Division, North Ryde, NSW 2113, Australia.
authors: Zheng-Zhou
authors: ZZ
authors: Xu
authors: CSIRO Preventative Health Flagship, Animal, Food & Health Sciences Division, North Ryde, NSW 2113, Australia.
authors: Peter L
authors: PL
authors: Molloy
authors: Department of Colorectal Surgery, Royal Melbourne Hospital, Parkville, VIC 3050, Australia.
authors: Ian T
authors: IT
authors: Jones
authors: Department of Colorectal Surgery, Western Hospital, Footscray, VIC 3011, Australia.
authors: Stephen
authors: S
authors: McLaughlin
authors: Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales, Sydney, NSW 2052, Australia.
authors: Robyn L
authors: RL
authors: Ward
authors: School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
authors: Nicholas J
authors: NJ
authors: Hawkins
authors: Department of Surgical Pathology, SA Pathology, Adelaide, SA 5000, Australia.
authors: Andrew R
authors: AR
authors: Ruszkiewicz
authors: Department of Colorectal Surgery, Royal Adelaide Hospital, Adelaide, SA 5000, Australia.
authors: James
authors: J
authors: Moore
authors: Faculty of Medicine, Dentistry and Health Sciences, Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.|Faculty of Medicine, Dentistry and Health Sciences, Department of Surgery, University of Melbourne, Parkville, VIC 3010, Australia.|Structural Biology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
authors: Antony W
authors: AW
authors: Burgess
authors: J. Craig Venter Institute Rockville, MD, 20850, USA.
authors: Dana
authors: D
authors: Busam
authors: Ludwig Collaborative Laboratory for Cancer Biology and Therapy, Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors: Qi
authors: Q
authors: Zhao
authors: Ludwig Collaborative Laboratory for Cancer Biology and Therapy, Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.|Ludwig Institute for Cancer Research Ltd., New York, NY 10017, USA.
authors: Robert L
authors: RL
authors: Strausberg
authors: Systems Biology and Personalised Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.|Department of Medical Oncology, Royal Melbourne Hospital, Parkville, VIC 3050, Australia.
authors: Lara
authors: L
authors: Lipton
authors: Systems Biology and Personalised Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.|Faculty of Medicine, Dentistry and Health Sciences, Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.|Department of Medical Oncology, Royal Melbourne Hospital, Parkville, VIC 3050, Australia.
authors: Jayesh
authors: J
authors: Desai
authors: Systems Biology and Personalised Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.|Faculty of Medicine, Dentistry and Health Sciences, Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.|Department of Medical Oncology, Royal Melbourne Hospital, Parkville, VIC 3050, Australia.
authors: Peter
authors: P
authors: Gibbs
authors: Systems Biology and Personalised Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.|Faculty of Medicine, Dentistry and Health Sciences, Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.
authors: Oliver M
authors: OM
authors: Sieber
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D000328:Adult; D000368:Aged; D058534:Class I Phosphatidylinositol 3-Kinases; D003110:Colonic Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D018899:CpG Islands; D018572:Disease-Free Survival; D005260:Female; D016158:Genes, p53; D011905:Genes, ras; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D018895:Microsatellite Repeats / Q000235:genetics*; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000401:mortality; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011379:Prognosis; D040081:Protein Array Analysis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics
chemical_list: C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf