| Purpose Malignant peripheral nerve sheath tumors(MPNST) are rare, highly malignant, and poorly understood sarcomas. Even with multidisciplinary treatment, the prognosis for patients with MPNST remains very poor. The often poor outcome of MPNST highlights the necessity of identifying prognostic predictors for this aggressive sarcoma. The fibroblast growth factor receptors(FGFRs) family play important roles in regulating cell growth, proliferation, survival, differentiation and angiogenesis. The therapies and related drugs which target at FGFR signaling pathway have made great progress in the field of tumor. Here, there are not so much study of the FGF/FGFR pathway have been conducted in MPNST, so in our study we investigate the role of fibroblast growth factor receptor(FGFR) family members in human MPNSTs.Method We performed microarray-based comparative genomic hybridization(a CGH) profiling of two cohorts of primary MPNST tissue samples including 25 patients treated at The University of Texas MD Anderson Cancer Center and 26 patients from Tianjin Medical University Cancer Institute & Hospital. Fluorescence in situ hybridization(FISH) was used to validate the gene amplification detected by a CGH analysis. Another independent cohort of 63 formalin-fixed paraffin-embedded MPNST samples(including 52 evaluable samples for FISH assay) was obtained to explore FGFR1, 2, 3, and 4 protein expression by immunohistochemical(IHC) analysis. Correlations between FGFR expression and clinicopathological variables were analyzed using the Chi-square test. Correlations between FGFR1 and FGFR1 and FGFRs were analyzed using the Spearman’s rank correlation coefficient.Patient survival curves were plotted according to the Kaplan–Meier method.Result 1. a CGH and bioinformatics analysis identified frequent amplification of the FGFR1 gene(37%), frequent deletion of FGFR2(41%) and FGFR3(27%),while no significant aberrations in the FGFR4 gene were detected by a CGH analysis.2. FISH analysis revealed that 26.9%(14/52) MPNST samples had amplification of FGFR1, with both focal and chromosomal arm level amplification(polysomy) patterns observed. NF1-positive cases had a higher frequency of FGFR1 gene amplification(χ2=5.091, p=0.024).3. IHC identified increased FGFR1 protein expression in 30.2%(19/63) of MPNST samples and this was positively correlated with FGFR1 gene amplification(χ2 = 4.924, p=0.026; r=0.308, p=0.026). High expression of FGFR1 protein was associated with better overall survival(OS) and was an independent prognostic predictor for OS of MPNST patients(HR=0.357, 95% CI=0.149–0.851, p= 0.020). Additionally, FGFR2 protein was detected in 19.7%(12/61) of MPNST cases. Combined expression of FGFR1 and FGFR2 protein characterized a subtype of MPNST with better OS(χ2=6.215, p=0.045; HR=0.394, 95% CI = 0.185–0.839, p=0.016). No FGFR3 protein expression was detected in MPNST samples. FGFR4 protein was expressed 82.3%(51/62) of MPNST samples, and was associated with poor disease-free survival(χ2=4.546, p=0.033).4. We further investigated the prognostic role of FGFR1 in MPNST by separating the 52 cases of MPNST samples based upon FGFR1 gene amplification, forming an amplified group(n=14) and a normal group(n=38). FGFR1 protein expression significantly influenced OS in the FGFR1-amplified group(χ2=5.311, p=0.021). We next regrouped patients based on FGFR1 and FGFR2 protein expression as follows: both positive, both negative,or single-positive for either. Patients expressing both FGFR1 and FGFR2 exhibited the best OS(χ2= 6.215, p=0.045).Conclusion Our study provides genetic evidence of FGFRs gene copy number alteration in MPNST. FGFR1 was amplified in MPNST and FGFR1 protein expression was an independent prognostic predictors of OS. FGFR4 was high expressed in MPNST and and also a prognostic predictor of DFS. We identified two molecular subsets of MPNST with distinct prognoses based on expression levels of FGFR1, FGFR2, and FGFR4. Our integrated genomic and molecular studies provide evidence that FGFRs play different prognostic roles in MPNST. |
