Aberrations Of TBX2-CHK2-p53 Pathway And Its Role In Malignant Peripheral Nerve Sheath Tumor

PurposeDetecting the aberrations of TBX2-CHK2-p53 signaling pathway and investigate its possible biological role in malignant peripheral nerve sheath tumors(MPNST).MethodWe selected 10 fresh cases of MPNST tissue samples with qualified DNA quality from Tianjin Medical University Cancer Institute & Hospital and performed Next Generation Sequencing(NGS)profiling to detect the genetic aberrations of TBX2-CHK2-p53 signaling pathway.Another independent cohort of 63 formalin-fixed paraffin-embedded(FFPE)MPNST samples(including 10 samples for NGS assay)was obtained to explore proteins expression of TBX2-CHK2-p53 signaling pathway by immunohistochemical(IHC)analysis.Meanwhile,protein expression levels of Ki-67 and cyclin D1 were detected to evaluate correlation of TBX2-CHK2-p53 signaling pathway with tumor cell proliferation and cell cycle in MPNST.The correlation of proteins expression with clinicopathological characteristics were determined by Chi-square test.Correlation analysis between proteins was evaluated by Spearman’s rank correlation.Kaplan–Meier method was used to analyse correlation between proteins expression and disease-free survival(DFS)and overall survival(OS).Cox proportional hazard method was used to identify independent predictors of survival.Result1.NGS and later bioinformatics analysis identified that,in 10 cases of MPNST tissue samples,there existed genes mutations of TBX2-CHK2-p53 signal pathway,including 1 intron mutation of TBX2,1 intron and 2 missense mutations of CHK2,2 intron,3 missense mutations and 1 frame shift deletion of p53.2.IHC identified that in 63 cases of MPNST tissue samples,there existed proteins expression of TBX2-CHK2-p53 signaling pathway.The rates of high TBX2,CHK2 and p53 expression were 60.3%(38/63),47.6%(30/63)and 30.2%(19/63),respectively.Patients with high TBX2,CHK2 and p53 expression exhibited a significantly shorter DFS than those with low expression of TBX2,CHK2 and p53,respectively(all p<0.05).Patients with high TBX2,CHK2 and p53 expression exhibited a significantly shorter OS than those with low expression of TBX2,CHK2 and p53,respectively(all p<0.05).TBX2 expression correlated with CHK2 expression positively(p < 0.05)and CHK2 expression had a positive relation with p53 expression(p<0.01).These results suggested that TBX2 and CHK2 might regulate each other and jointly promote the occurrence and progress of MPNST.3.IHC also identified both CHK2 and p53 expression correlated with the Ki-67 expression positively(both p<0.05),suggesting TBX2-CHK2-p53 signaling pathway may involve in the occurrence and development of MPNST by promoting cell proliferation of MPNST.4.Multivariate analysis showed that TBX2 and CHK2 were independent prognostic factors of MPNST patients(both p<0.05),indicating that they may be used as important indicators to judge the prognosis of MPNST.ConclusionOur study found there existed genes mutations of TBX2,CHK2 and p53 in TBX2-CHK2-p53 signaling pathway.Abnormal proteins expression of TBX2-CHK2-p53 signaling pathway might involve in the occurrence and development of MPNST by promoting cell proliferation of MPNST,and the prognosis was poor.So in MPNST,TBX2-CHK2-p53 signaling pathway was abnormal and had important biological significance.TBX2 and CHK2 may be potential prognostic factors and targets for targeted therapy.