title: STAT3 expression, molecular features, inflammation patterns, and prognosis in a database of 724 colorectal cancers.
abstract: OBJECTIVE
  STAT3 is a transcription factor that is constitutively activated in some cancers. It seems to play crucial roles in cell proliferation and survival, angiogenesis, tumor-promoting inflammation, and suppression of antitumor host immune response in the tumor microenvironment. Although the STAT3 signaling pathway is a potential drug target, clinical, pathologic, molecular, or prognostic features of STAT3-activated colorectal cancer remain uncertain.
  
  
  METHODS
  Utilizing a database of 724 colon and rectal cancer cases, we evaluated phosphorylated STAT3 (p-STAT3) expression by immunohistochemistry. The Cox proportional hazards model was used to compute mortality HR, adjusting for clinical, pathologic, and molecular features, including microsatellite instability (MSI), the CpG island methylator phenotype (CIMP), LINE-1 methylation, 18q LOH, TP53 (p53), CTNNB1 (β-catenin), JC virus T-antigen, and KRAS, BRAF, and PIK3CA mutations.
  
  
  RESULTS
  Among the 724 tumors, 131 (18%) showed high-level p-STAT3 expression (p-STAT3-high), 244 (34%) showed low-level expression (p-STAT3-low), and the remaining 349 (48%) were negative for p-STAT3. p-STAT3 overexpression was associated with significantly higher colorectal cancer-specific mortality [log-rank P = 0.0020; univariate HR (p-STAT3-high vs. p-STAT3-negative): 1.85, 95% CI: 1.30-2.63, P(trend) = 0.0005; multivariate HR: 1.61, 95% CI: 1.11-2.34, P(trend) = 0.015]. p-STAT3 expression was positively associated with peritumoral lymphocytic reaction (multivariate OR: 3.23; 95% CI: 1.89-5.53, P < 0.0001). p-STAT3 expression was not associated with MSI, CIMP, or LINE-1 hypomethylation.
  
  
  CONCLUSIONS
  STAT3 activation in colorectal cancer is associated with adverse clinical outcome, supporting its potential roles as a prognostic biomarker and a chemoprevention and/or therapeutic target.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Teppei
authors.initials: T
authors.lastname: Morikawa
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Baba
authors.forename: Mai
authors.initials: M
authors.lastname: Yamauchi
authors.forename: Aya
authors.initials: A
authors.lastname: Kuchiba
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Nosho
authors.forename: Kaori
authors.initials: K
authors.lastname: Shima
authors.forename: Noriko
authors.initials: N
authors.lastname: Tanaka
authors.forename: Curtis
authors.initials: C
authors.lastname: Huttenhower
authors.forename: David A
authors.initials: DA
authors.lastname: Frank
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
authors.forename: Shuji
authors.initials: S
authors.lastname: Ogino
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000378:metabolism*; D018899:CpG Islands; D019175:DNA Methylation; D030562:Databases, Protein; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007249:Inflammation; D019656:Loss of Heterozygosity; D008214:Lymphocytes / Q000378:metabolism; D015999:Multivariate Analysis; D011379:Prognosis; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D011795:Surveys and Questionnaires
chemical_list: D014408:Biomarkers, Tumor; D050796:STAT3 Transcription Factor