title: EGFR, HER2, survivin, and loss of pSTAT3 characterize high-grade malignancy in salivary gland cancer with impact on prognosis.
abstract: Increased gene copy number (high polysomy or amplification) of EGFR and HER2 has evolved as a predictor for response to targeted therapy. STAT3 and the apoptosis inhibitor survivin represent distinct oncogenes in various human neoplasms. The purpose of this study was to evaluate protein and gene status of these biomarkers by immunohistochemistry and dual color fluorescence in situ hybridization on tissue microarrays of 286 salivary gland carcinomas in the context of clinical and histopathologic characteristics. Diverse tumor types showed overexpression and increased gene copy number of EGFR and HER2. Amplification of HER2 was found in 35.5% of salivary duct carcinomas. Protein overexpression was strongly associated with high gene copy number for both EGFR and HER2 (P < .001). Overexpression and increased gene copy number of EGFR and HER2 were correlated to high-grade malignancy (P < .001) and unfavorable prognosis (P < .001). Strong nuclear staining of survivin was found in 18.9% of tumors and was associated with high-grade malignancy (P < .001), overexpression, and high gene copy number of EGFR and HER2 (P ≤ .05) as well as unfavorable prognosis (P < .001). Overexpression of nuclear pSTAT3 was found in 28.3% of tumors and correlated with well tumor differentiation (P < .001) and favorable prognosis (P = .001). Loss or weak expression of pSTAT3 was inversely associated with overexpression of survivin (P < .001) as well as overexpression and high gene copy number of EGFR and HER2 (P < .05). Overall, overexpression and increased gene copy number of EGFR and HER2 characterize high-grade malignancy with unfavorable prognosis in salivary gland cancer. Nuclear survivin typifies aggressive tumors with worse prognosis, whereas nuclear pSTAT3 might play a role as a tumor suppressor in absence of EGFR, HER2, and survivin.
authors.affiliation: Department of Oral and Maxillofacial Surgery, University of Regensburg, Franz-Josef-Strauβ-Allee 11, 93053 Regensburg, Germany. tobias.ettl@klinik.uni-regensburg.de
authors.forename: Tobias
authors.initials: T
authors.lastname: Ettl
authors.forename: Clemens
authors.initials: C
authors.lastname: Stiegler
authors.forename: Katharina
authors.initials: K
authors.lastname: Zeitler
authors.forename: Abbas
authors.initials: A
authors.lastname: Agaimy
authors.forename: Johannes
authors.initials: J
authors.lastname: Zenk
authors.forename: Torsten E
authors.initials: TE
authors.lastname: Reichert
authors.forename: Martin
authors.initials: M
authors.lastname: Gosau
authors.forename: Thomas
authors.initials: T
authors.lastname: Kühnel
authors.forename: Gero
authors.initials: G
authors.lastname: Brockhoff
authors.forename: Stephan
authors.initials: S
authors.lastname: Schwarz
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D066246:ErbB Receptors / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D018773:Genes, erbB-1; D018734:Genes, erbB-2; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D051034:Inhibitor of Apoptosis Proteins / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D053208:Kaplan-Meier Estimate; D008297:Male; D009367:Neoplasm Staging; D011379:Prognosis; D016016:Proportional Hazards Models; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D012468:Salivary Gland Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000077022:Survivin; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; D066246:ErbB Receptors; D051034:Inhibitor of Apoptosis Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D050796:STAT3 Transcription Factor; D000077022:Survivin; C107489:BIRC5 protein, human; C494086:STAT3 protein, human; C512478:EGFR protein, human