title: CD44 and OTP are strong prognostic markers for pulmonary carcinoids.
abstract: OBJECTIVE
  Pulmonary carcinoids are well-differentiated neuroendocrine tumors showing usually a favorable prognosis. However, there is a risk for late recurrence and/or distant metastasis. Because histologic classification in typical and atypical carcinoids is difficult and its reliability to predict disease outcome varies, we evaluated three genes as potential prognostic markers, that is, orthopedia homeobox (OTP), CD44, and rearranged during transfection (RET).
  
  
  METHODS
  These genes were analyzed in 56 frozen carcinoids by quantitative real-time PCR (qRT-PCR). RET was further studied by methylation and mutation analysis. Immunohistochemistry for CD44 and OTP protein expression was conducted on 292 carcinoids.
  
  
  RESULTS
  Low mRNA expression levels of CD44 (P = 1.8e(-5)) and OTP (P = 0.00054), and high levels of RET (P = 0.025), were strongly associated with a low 20-year survival of carcinoid patients. High RET expression was not related to promoter hypomethylation or gene mutations. A direct link between gene expression and protein levels was confirmed for CD44 and OTP but not for RET. Within all carcinoids as well as atypical carcinoids, absence of CD44 protein was significantly associated with low 20-year survival (P = 0.00014 and 0.00013, respectively). The absence of nuclear OTP followed by complete loss of expression was also significantly associated with unfavorable disease outcome in all carcinoids (P = 5.2(-6)). Multivariate analyses revealed that age at diagnosis, histopathology, stage, and cytoplasmic OTP immunoreactivity were independent predictors of prognosis.
  
  
  CONCLUSIONS
  Our study indicates that CD44 and OTP are strong indicators of poor outcome. We therefore argue for implementation of these markers in routine diagnostics in addition to histopathology to improve subclassification of pulmonary carcinoids into prognostically relevant categories.
authors: Department of Molecular Cell Biology, GROW-School for Oncology & Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands. d.swarts@maastrichtuniversity.nl
authors: Dorian R A
authors: DR
authors: Swarts
authors: Mieke E R
authors: ME
authors: Henfling
authors: Leander
authors: L
authors: Van Neste
authors: Robert-Jan
authors: RJ
authors: van Suylen
authors: Anne-Marie C
authors: AM
authors: Dingemans
authors: Winand N M
authors: WN
authors: Dinjens
authors: Annick
authors: A
authors: Haesevoets
authors: Martina
authors: M
authors: Rudelius
authors: Erik
authors: E
authors: Thunnissen
authors: Marco
authors: M
authors: Volante
authors: Wim
authors: W
authors: Van Criekinge
authors: Manon
authors: M
authors: van Engeland
authors: Frans C S
authors: FC
authors: Ramaekers
authors: Ernst-Jan M
authors: EJ
authors: Speel
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002276:Carcinoid Tumor / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics* / Q000378:metabolism; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D018398:Homeodomain Proteins; D018960:Hyaluronan Receptors; D009419:Nerve Tissue Proteins; C490261:OTP protein, human; D051096:Proto-Oncogene Proteins c-ret