Mutation And Value Of TERT?ATRX In WHO ?-? Glioma

Background: Gliomas are the most common primary tumors of the central nervous system.The incidence in China is about 7 / 100,000.The characteristics of gliomas are difficult surgical resection,rapid progression of the disease and short survival time.With the development of molecular pathology,many molecular markers have been proved to be associated with gliomas,and these molecular markers play an important guiding role in the clinical treatment of gliomas.The 1p / 19 q and IDH molecular markers are found relatively early and have been included in the 4th edition of the CNS tumor classification revised by the World Health Organization(WHO)in 2016.Mutations in the two telomerase reverse transcriptase(TERT)and alpha thalassemia / psychotropic syndrome X-linked(ATRX)genes are also many of the hallmarks of glioma classification and prognosis theme.Telomeres are nucleoprotein complexes at the ends of all eukaryotic chromosomes made up of hundreds of nucleotide repeats,with their length gradually diminished with each mitosis.Telomerase is a reverse transcriptase that uses its own RNA molecule as a template to add nucleotides to telomere replication.Tumors maintain their telomere length by either reactivating telomerase or by a mechanism of telomerase(collectively referred to as alternative telomere elongation)(ALT).The discovery of mutations in the core region of the TERT promoter in gliomas and many other tumors is a major cause of increased telomerase activity.Many ATRX mutations exist in tumors with surrogate telomere extensions,which bind the H3.3 histone to the central component of the chromatin remodeling complex required in telomeres.The incidence of ATRX mutations in grade II-III glioma and secondary glioblastoma is approximately 75%.Therefore,the mutation of them has great significance for researching the formation and development of glioma.The number of studies aiming at mechanism of telomere maintenance of glioma is growing.These studies are very meaningful for clinical prognosis and prognosis,which may guide the clinical treatment of glioma patients.However,so far,no study has explicitly analyzed the importance of ATRX changes and TERT promoter mutations between diagnostic entities in the WHO 2016 classification.The purpose of this study was to assess the significance of ATRX changes in glioma markers and the expression of TERT promoter mutations in grade II-III glioma.OBJECTIVE:To detect the TERT promoter region and ATRX mutation in 179glioma tissues by Sanger sequencing and immunohistochemistry,and to evaluate its significance in gliomas of WHO class II-IV.To explore the relationship between the expression level and tumor origin,progression and invasion mechanism.Methods:We collected tumor tissues from 2016 to 2017 at Tianjin Huanhu Hospital.According to the human glioma genome database in China,more than 80%of the tissue was tumor tissue.All of the specimens were diagnosed by an experienced pathologist.The study was approved by the Medical Ethics Committee of Tianjin Huanshu Hospital,and all of the patients signed informed consent forms.Criteria:(1)Specimens were clearly diagnosed with glioma by pathology using the 2016 version of the“WHO central nervous system tumor classification”for grades II-IV.(2)The pathology library had complete and adequate paraffin specimens.Exclusion criteria:(1)Tissues of poor quality.(2)WHO grade I(low grade)glioma.After screening,the total number of cases was 179,including 38 WHO class II glioma cases,43 grade III cases,and 98 grade IV cases(108 males,71 females;age range 8 to 84 years,median age 48.5 years).Result:1.We found that the TERT promoter mutation showed a positive correlation with age(P <0.05).WHO classification showed a positive correlation(P <0.05),which was correlated with ATRX mutation(P <0.001).Therefore,this study further used the binary Logistic regression to evaluate the influence of age,gender,WHO classification,IDH mutation,MGMT methylation,Ki-67 protein expression index ATRX mutation to TERT promoter mutation.Finally,the Logistic model was statistically significant.2.The positive rate of ATRX mutation in WHO grade II glioma was 44.74%(17/38).The positive rate of ATRX mutation in WHO grade III glioma was 44.18(19 / 43).In WHO grade IV gliomas,the positive rate of ATRX mutation was 27.55(27/98).We further analyzed the influence of age,sex,WHO classification,IDH mutation,MGMT methylation,Ki-67 protein expression index by using Logistic regression.Finally,the Logistic model was statistically significant.3.We added the ATRX mutation to the typing of TERT promoter mutations to observe the relationship with Ki-67 protein expression index.We found that TERT promoter mutations showed significant differences in the ATRX mutation group and the wild group(p <0.05).In the TERT wild-type group,patients with ATRX deletion had the lowest expression of Ki-67 protein,while those without ATRX deletion had the highest expression of Ki-67 protein in four groups.4.We further studied the relationship between IDH mutation and TERT mutation.We found that the mutation rate of IDH was decreased with the increasing of tumor grade,and the positive rate in high-grade glioma(grade ?)was significantly lower than WHO II,III glioma.TERT promoter mutations(grade ?-?)were significantly higher than those of low grade gliomas(grade ?).Conclusion: This study shows that TERT promoter region and ATRX mutation have significant prognostic significance for the prognosis of gliomas.