title: SMO expression in colorectal cancer: associations with clinical, pathological, and molecular features.
abstract: BACKGROUND
  Smoothened, frizzled family receptor (SMO) is an important component of the hedgehog signaling pathway, which has been implicated in various human carcinomas. However, clinical, molecular, and prognostic associations of SMO expression in colorectal cancer remain unclear.
  
  
  METHODS
  Using a database of 735 colon and rectal cancers in the Nurse's Health Study and the Health Professionals Follow-up Study, we examined the relationship of tumor SMO expression (assessed by immunohistochemistry) to prognosis, and to clinical, pathological, and tumor molecular features, including mutations of KRAS, BRAF, and PIK3CA, microsatellite instability, CpG island methylator phenotype (CIMP), LINE-1 methylation, and expression of phosphorylated AKT and CTNNB1.
  
  
  RESULTS
  SMO expression was detected in 370 tumors (50 %). In multivariate logistic regression analysis, SMO expression was independently inversely associated with phosphorylated AKT expression [odds ratio (OR) 0.48; 95 % confidence interval (CI) 0.34-0.67] and CTNNB1 nuclear localization (OR 0.48; 95 % CI 0.35-0.67). SMO expression was not significantly associated with colorectal cancer-specific or overall survival. However, in CIMP-high tumors, but not CIMP-low/0 tumors, SMO expression was significantly associated with better colorectal cancer-specific survival (log-rank P = 0.012; multivariate hazard ratio, 0.36; 95 % CI 0.13-0.95; P interaction = 0.035, for SMO and CIMP status).
  
  
  CONCLUSIONS
  Our data reveal novel potential associations between the hedgehog, the WNT/CTNNB1, and the PI3K (phosphatidylinositol-4,5-bisphosphonate 3-kinase)/AKT pathways, supporting pivotal roles of SMO and hedgehog signaling in pathway networking. SMO expression in colorectal cancer may interact with tumor CIMP status to affect patient prognosis, although confirmation by future studies is needed.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
authors.forename: Tingting
authors.initials: T
authors.lastname: Li
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Liao
authors.forename: Paul
authors.initials: P
authors.lastname: Lochhead
authors.forename: Teppei
authors.initials: T
authors.lastname: Morikawa
authors.forename: Mai
authors.initials: M
authors.lastname: Yamauchi
authors.forename: Reiko
authors.initials: R
authors.lastname: Nishihara
authors.forename: Kentaro
authors.initials: K
authors.lastname: Inamura
authors.forename: Sun A
authors.initials: SA
authors.lastname: Kim
authors.forename: Kosuke
authors.initials: K
authors.lastname: Mima
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Sukawa
authors.forename: Aya
authors.initials: A
authors.lastname: Kuchiba
authors.forename: Yu
authors.initials: Y
authors.lastname: Imamura
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Baba
authors.forename: Kaori
authors.initials: K
authors.lastname: Shima
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Meyerhardt
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Chan
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
authors.forename: Shuji
authors.initials: S
authors.lastname: Ogino
authors.forename: Zhi Rong
authors.initials: ZR
authors.lastname: Qian
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D053823:Hedgehog Proteins / Q000235:genetics; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011379:Prognosis; D011446:Prospective Studies; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D015398:Signal Transduction; D000072086:Smoothened Receptor; D014481:United States; D051176:beta Catenin / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C495270:CTNNB1 protein, human; D053823:Hedgehog Proteins; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor; D051176:beta Catenin; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins