title: The clinical correlation of phosphatase and tensin homolog on chromosome 10, phosphorylation of AKT to an activated state, and odontogenic ameloblast-associated protein in gastrointestinal stromal tumors.
abstract: Approximately 15% of gastrointestinal stromal tumors (GISTs) will not respond to tyrosine kinase inhibitors and drug resistance can develop over time. For refractory tumors, additional therapies are needed. Odontogenic ameloblast-associated protein (ODAM) is expressed in some epithelial malignancies and can correlate with clinical outcomes. This study evaluated ODAM and its relationship to phosphatase and tensin homolog on chromosome 10 (PTEN) and phosphorylation of AKT to an activated state (pAKT) in GISTs.
  
  
  
  Ninety-five distinct tumor specimens from 79 patients were identified. Morphologic features and clinical data were recorded for all tumors. Risk of recurrence was calculated using the Memorial Sloan-Kettering nomogram. Immunohistochemistry was performed using antibodies to ODAM, PTEN, and pAKT. Immunoreactivity was assessed for both cytoplasmic and nuclear expression. Staining patterns were correlated with clinical outcomes.
  
  
  
  Increasing cytoplasmic ODAM staining correlated with a lower recurrence score (P = 0.002), a lower mitotic rate (P = 0.0001), and smaller tumor size (P = 0.038). Increasing pAKT cytoplasmic staining correlated with a higher recurrence score (P = 0.037) and a higher mitotic rate (P = 0.036). ODAM and pAKT expression in the nucleus was associated with tumor origin. PTEN nuclear expression increased with increasing mitotic rate. pAKT expression increased in the cytoplasm and nucleus in high-risk tumors.
  
  
  
  Risk of recurrence correlated with cytoplasmic expression of ODAM and pAKT, whereas nuclear expression did not predict recurrence. The staining pattern for ODAM and pAKT in the cytoplasm may further clarify the risk of recurrence beyond the available nomograms. The increased expression of pAKT in the cytoplasm and nucleus of high-risk tumors suggests a potential target for systemic therapy.
authors.affiliation: Department of Surgery, University of Tennessee Medical Center, Knoxville, Tennessee. Electronic address: jmcloughlin@utmck.edu.
authors.forename: James
authors.initials: J
authors.lastname: McLoughlin
authors.affiliation: Department of Pathology, University of Tennessee Medical Center, Knoxville, Tennessee.
authors.forename: Laurentia
authors.initials: L
authors.lastname: Nodit
authors.affiliation: Department of Biostatistics, University of Tennessee Medical Center, Knoxville, Tennessee.
authors.forename: R Eric
authors.initials: RE
authors.lastname: Heidel
authors.affiliation: Department of Pathology, University of Tennessee Medical Center, Knoxville, Tennessee.
authors.forename: Stuart
authors.initials: S
authors.lastname: Van Meter
authors.affiliation: University of Tennessee Medical Center, Graduate School of Medicine, Knoxville, Tennessee.
authors.forename: Sallie
authors.initials: S
authors.lastname: Macy
authors.affiliation: University of Tennessee Medical Center, Graduate School of Medicine, Knoxville, Tennessee.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kestler
mesh_terms: D000682:Amyloid; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D005260:Female; D005500:Follow-Up Studies; D005770:Gastrointestinal Neoplasms / Q000378:metabolism* / Q000401:mortality; D046152:Gastrointestinal Stromal Tumors / Q000378:metabolism* / Q000401:mortality; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D016015:Logistic Models; D008297:Male; D009363:Neoplasm Proteins; D009364:Neoplasm Recurrence, Local / Q000378:metabolism* / Q000401:mortality; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D010766:Phosphorylation; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012042:Registries; D012189:Retrospective Studies; D016019:Survival Analysis
chemical_list: D000682:Amyloid; D014408:Biomarkers, Tumor; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; C480049:ODAM protein, human; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: GIST; Gastrointestinal tumors; ODAM; PTEN; pAKT