A three-gene signature for outcome in soft tissue sarcoma.
OBJECTIVE
Finding markers or gene sets that would further classify patients into different risk categories and thus allow more individually adapted multimodality treatment regimens in soft tissue sarcomas is necessary. In this study, we investigated the prognostic values of hypoxia-inducible factor 1a (HIF1a), heparin-binding epidermal growth factor-like growth factor (HB-EGF), vascular endothelial growth factor (VEGF), and other angiogenesis-related gene expressions, as well as their interrelationships.


METHODS
Formalin-fixed paraffin-embedded tissue samples were obtained from 45 patients with soft tissue sarcoma (median age 57 years, range 16-85 years). After laser capture microdissection direct quantitative real-time reverse transcription-PCR (TaqMan) assays were done in triplicates to determine HIF1a, HB-EGF, VEGF, and other gene expression levels.


RESULTS
Multivariate Cox [corrected] regression analysis revealed significant independent associations of HB-EGF, HIF1a, and VEGF-C gene expression to the overall survival (P < 0.0001). A combined factor of these three genes showed a relative risk for shorter survival of 5.5, more than twice higher as in an increasing International Union against Cancer Stage. Receiver operating characteristic curve analysis showed a significant sensitivity of 73% and specificity of 82% of this factor for the diagnosis of short (<3 years) versus long (3-9 years) survival (P = 0.0002). VEGF-A showed significant gender differences in the association to survival.


CONCLUSIONS
Measuring HIF1a, HB-EGF, and VEGF-C expression may contribute to a better understanding of the prognosis of patients with soft tissue sarcoma and may even play a crucial role for the distribution of patients to multimodal therapeutic regimens. Prospective studies investigating the response to different adjuvant or palliative therapies seem to be warranted.
Hoffmann
Andreas-Claudius
AC
Department of Medicine (Cancer Research), West German Cancer Center, Molecular Oncology Risk-Profile Evaluation, University Hospital Essen, Essen, Germany. ach@o117.com
Hoffman
Andreas-Claudius
AC
Danenberg
Kathleen D
KD
Taubert
Helge
H
Danenberg
Peter V
PV
Wuerl
Peter
P
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011379:Prognosis; D012509:Sarcoma / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D012680:Sensitivity and Specificity; D016019:Survival Analysis; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics*; D055815:Young Adult
C587883:HBEGF protein, human; C497442:HIF1A protein, human; D066257:Heparin-binding EGF-like Growth Factor; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins; D042582:Vascular Endothelial Growth Factor C