PMID- 26446941
OWN - NLM
STAT- MEDLINE
DCOM- 20161025
LR  - 20181113
IS  - 1557-3265 (Electronic)
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 22
IP  - 3
DP  - 2016 Feb 1
TI  - A Composite Gene Expression Signature Optimizes Prediction of Colorectal Cancer 
      Metastasis and Outcome.
PG  - 734-45
LID - 10.1158/1078-0432.CCR-15-0143 [doi]
AB  - PURPOSE: We previously found that an epithelial-to-mesenchymal transition 
      (EMT)-based gene expression signature was highly correlated with the first 
      principal component (PC1) of 326 colorectal cancer tumors and was prognostic. 
      This study was designed to improve these signatures for better prediction of 
      metastasis and outcome. EXPERIMENTAL DESIGN: A total of 468 colorectal cancer 
      tumors including all stages (I-IV) and metastatic lesions were used to develop a 
      new prognostic score (DeltaPC1.EMT) by subtracting the EMT signature score from its 
      correlated PC1 signature score. The score was validated on six other independent 
      datasets with a total of 3,697 tumors. RESULTS: DeltaPC1.EMT was found to be far more 
      predictive of metastasis and outcome than its parent scores. It performed well in 
      stages I to III, among microsatellite instability subtypes, and across multiple 
      mutation-based subclasses, demonstrating a refined capacity to predict distant 
      metastatic potential even in tumors with a "good" prognosis. For example, in the 
      PETACC-3 clinical trial dataset, it predicted worse overall survival in an 
      adjusted multivariable model for stage III patients (HR standardized by 
      interquartile range [IQR] = 1.50; 95% confidence interval, 1.25-1.81; P = 
      0.000016, N = 644). The improved performance of DeltaPC1.EMT was related to its 
      propensity to identify epithelial-like subpopulations as well as mesenchymal-like 
      subpopulations. Biologically, the signature was correlated positively with RAS 
      signaling but negatively with mitochondrial metabolism. DeltaPC1.EMT was a "best of 
      assessed" prognostic score when compared with 10 other known prognostic 
      signatures. CONCLUSIONS: The study developed a prognostic signature score with a 
      propensity to detect non-EMT features, including epithelial cancer stem 
      cell-related properties, thereby improving its potential to predict metastasis 
      and poorer outcome in stage I-III patients.
CI  - (c)2015 American Association for Cancer Research.
FAU - Schell, Michael J
AU  - Schell MJ
AD  - Moffitt Cancer Center & Research Institute, Tampa, Florida. Yeatman@gibbscc.org 
      Michael.schell@moffitt.org.
FAU - Yang, Mingli
AU  - Yang M
AD  - Gibbs Cancer Center & Research Institute, Spartanburg, South Carolina.
FAU - Missiaglia, Edoardo
AU  - Missiaglia E
AD  - SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland.
FAU - Delorenzi, Mauro
AU  - Delorenzi M
AD  - SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland. Ludwig Center for 
      Cancer Research, University of Lausanne (CH), Lausanne, Switzerland. Department 
      of Oncology, University of Lausanne (CH), Lausanne, Switzerland.
FAU - Soneson, Charlotte
AU  - Soneson C
AD  - SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland.
FAU - Yue, Binglin
AU  - Yue B
AD  - Moffitt Cancer Center & Research Institute, Tampa, Florida.
FAU - Nebozhyn, Michael V
AU  - Nebozhyn MV
AD  - Merck, Sharp and Dohme, West Point, Pennsylvania.
FAU - Loboda, Andrey
AU  - Loboda A
AD  - Merck, Sharp and Dohme, West Point, Pennsylvania.
FAU - Bloom, Gregory
AU  - Bloom G
AD  - Moffitt Cancer Center & Research Institute, Tampa, Florida.
FAU - Yeatman, Timothy J
AU  - Yeatman TJ
AD  - Gibbs Cancer Center & Research Institute, Spartanburg, South Carolina. 
      Yeatman@gibbscc.org Michael.schell@moffitt.org.
LA  - eng
GR  - P30 CA076292/CA/NCI NIH HHS/United States
GR  - U01 CA157960/CA/NCI NIH HHS/United States
GR  - P30-CA76292/CA/NCI NIH HHS/United States
GR  - U01CA157960/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20151007
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
SB  - IM
MH  - Cluster Analysis
MH  - Colorectal Neoplasms/*diagnosis/*genetics/mortality
MH  - Epithelial-Mesenchymal Transition/genetics
MH  - Female
MH  - *Gene Expression Profiling
MH  - Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Kaplan-Meier Estimate
MH  - Male
MH  - Microsatellite Instability
MH  - Neoplasm Metastasis
MH  - Neoplasm Staging
MH  - Patient Outcome Assessment
MH  - Prognosis
MH  - Proportional Hazards Models
MH  - Reproducibility of Results
MH  - *Transcriptome
PMC - PMC4802496
MID - NIHMS732931
COIS- Competing financial interests: M.J.S and T.J.Y report involvement as part of a 
      provisional patent submitted to The United States Patent and Trademark Office, 
      during the conduct of the study. All other authors declare no competing financial 
      interests.
EDAT- 2015/10/09 06:00
MHDA- 2016/10/26 06:00
PMCR- 2017/02/01
CRDT- 2015/10/09 06:00
PHST- 2015/01/17 00:00 [received]
PHST- 2015/06/30 00:00 [accepted]
PHST- 2015/10/09 06:00 [entrez]
PHST- 2015/10/09 06:00 [pubmed]
PHST- 2016/10/26 06:00 [medline]
PHST- 2017/02/01 00:00 [pmc-release]
AID - 1078-0432.CCR-15-0143 [pii]
AID - 10.1158/1078-0432.CCR-15-0143 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2016 Feb 1;22(3):734-45. doi: 10.1158/1078-0432.CCR-15-0143. 
      Epub 2015 Oct 7.