title: Methylated TIMP-3 DNA in body fluids is an independent prognostic factor for gastric cancer.
abstract: BACKGROUND
  Fluid methylated DNA may be a suitable biomarker for cancer patients.
  
  
  OBJECTIVE
  To investigate whether circulating methylated tissue inhibitor of metalloproteinase 3 (TIMP-3) DNA in body fluids is a useful prognostic biomarker in gastric cancer (GC).
  
  
  METHODS
  TIMP-3 methylation was detected by real-time methylation-specific polymerase chain reaction in tumor tissues, paired preoperative peritoneal washes (PPWs), and paired serum samples from 92 GC patients.
  
  
  RESULTS
  The frequency of TIMP-3 methylation was significantly elevated in GC tissues (63.04%; 58 of 92) compared with that in paired adjacent normal tissue (4.3%; 4 of 92) (P < .001). TIMP-3 methylation correlated closely with peritoneal metastasis and TNM stage (all P < .001). The frequency of TIMP-3 methylation in preoperative peritoneal washes and serum samples was 53.3% (49 of 92) and 58.7% (54 of 92), respectively. The Aζ values of the receiver operator characteristic curve for methylated TIMP-3 were 0.966 and 0.922 for serum and preoperative peritoneal washes, respectively, compared with those in GC tissues. The patients with elevated methylated TIMP-3 levels in body fluids had poorer disease-free survival rates than those without (all P < .001). Cox regression analysis showed that detection of methylated TIMP-3 DNA in body fluids was an independent risk factor for GC patients, with a remarkable decrease in disease-free survival 30 months after surgical resection of the gastric tumor.
  
  
  CONCLUSIONS
  Presence of methylated TIMP-3 DNA in body fluids is a useful biomarker for predicting the progression and prognosis of GC patients.
authors.affiliation: From the Zhejiang Cancer Research Institute (Drs Yu, Han, X. Zhu, Wu, Hong, and Ling) and the Department of Surgical Oncology (Dr Wang), Zhejiang Province Cancer Hospital, Zhejiang Cancer Center, Hangzhou, China; the Department of Surgical Oncology (Dr Lv) and the Central Laboratory (Dr W-Y Zhu), Zhoushan Hospital, Zhoushan, China; and the Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China (Dr Li).
authors.forename: Jiang-Liu
authors.initials: JL
authors.lastname: Yu
authors.forename: Ping
authors.initials: P
authors.lastname: Lv
authors.forename: Jing
authors.initials: J
authors.lastname: Han
authors.forename: Xin
authors.initials: X
authors.lastname: Zhu
authors.forename: Lian-Lian
authors.initials: LL
authors.lastname: Hong
authors.forename: Wang-Yu
authors.initials: WY
authors.lastname: Zhu
authors.forename: Xin-Bao
authors.initials: XB
authors.lastname: Wang
authors.forename: Yi-Chen
authors.initials: YC
authors.lastname: Wu
authors.forename: Pei
authors.initials: P
authors.lastname: Li
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Ling
mesh_terms: D000328:Adult; D000368:Aged; D001202:Ascitic Fluid / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D018450:Disease Progression; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011401:Promoter Regions, Genetic; D060888:Real-Time Polymerase Chain Reaction; D012307:Risk Factors; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3