title: Gain of function of mutant TP53 in glioblastoma: prognosis and response to temozolomide.
abstract: OBJECTIVE
  Our aim was to investigate the relationship between mutant p53 and the prognosis of malignant glioma treated with temozolomide, and the regulation of mutant TP53 induced drug resistance, by molecular experimentation and a clinical trial.
  
  
  METHODS
  Adult patients with newly surgical diagnosed glioblastoma were randomly assigned to receive either temozolomide or semustine after radiation treatment. The statuses of TP53 and expression of TP53 and O(6)-methylguanine DNA-methyltransferase (MGMT) were determined retrospectively in tumor tissue from enrolled patients. The primary end point was overall survival. Synthetic small interfering RNA was used to knock down mutant TP53 in T98G and U138 cells, which are human glioblastoma cells with a P53 mutation, by screening of exons 4-8. Viable cell survival was measured when these cells were exposed to temozolomide or semustine. Expression of MGMT at the messenger RNA level was also determined.
  
  
  RESULTS
  The overall survival was 34.3 % at 2 years, 22.9 % at 3 years, 11.4 % at 4 years, and 8.6 % at 5 years with temozolomide, versus 18.2, 12.1, 3.0, and 0 %, respectively, with semustine. TP53 mutation and expression of mutant TP53 and MGMT showed significant inverse correlations with overall survival. Knockdown of mutant TP53 led to a fivefold increase in chemosensitivity to temozolomide but not semustine. Mutant TP53 knockdown induced down-regulation of MGMT expression.
  
  
  CONCLUSIONS
  Mutant TP53 is strongly associated with a poor prognosis for overall survival in patients with glioblastoma. Also, TP53 mutation may decrease the chemosensitivity of glioblastoma to temozolomide by increasing MGMT expression.
authors.affiliation: Department of Neurosurgery, West China Hospital of Sichuan University, Chengdu, China, wangxiangtim@gmail.com.
authors.forename: Xiang
authors.initials: X
authors.lastname: Wang
authors.forename: Jin-Xiu
authors.initials: JX
authors.lastname: Chen
authors.forename: Jin-Ping
authors.initials: JP
authors.lastname: Liu
authors.forename: Chao
authors.initials: C
authors.lastname: You
authors.forename: Yan-Hui
authors.initials: YH
authors.lastname: Liu
authors.forename: Qing
authors.initials: Q
authors.lastname: Mao
mesh_terms: D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D015254:DNA Modification Methylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011379:Prognosis; D034741:RNA, Small Interfering / Q000235:genetics; D012189:Retrospective Studies; D015996:Survival Rate; D000077204:Temozolomide; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D018906:Antineoplastic Agents, Alkylating; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide