title: DNA methyltransferase 1 as a predictive biomarker and potential therapeutic target for chemotherapy in gastric cancer.
abstract: OBJECTIVE
  DNA methylation contributes to carcinogenesis by mediating transcriptional regulation and chromatin remodelling, which may influence the effect of DNA-damaging drugs. We examined the prognostic and predictive impact of DNA methyltransferase (DNMT) 1 and 3b expression in gastric carcinomas (GC) treated by neoadjuvant chemotherapy. In vitro, DNMT1 expression and chemosensitivity were investigated for a functional relationship and the DNMT inhibitor decitabine (DAC) was tested as an alternative treatment option.
  
  
  METHODS
  DNMT1/3b expression was analysed immunohistochemically in 127 pretherapeutic biopsies of neoadjuvant (platinum/5-fluorouracil)-treated GC patients and correlated with response and overall survival (OS). Short hairpin RNA technology was used to knockdown DNMT1 in the GC cell line, AGS. The chemosensitivity of GC cell lines to DAC alone and to DAC in combination with cisplatin was analysed by XTT or colony formation assays.
  
  
  RESULTS
  High DNMT1 and DNMT3b expression was found in 105/127 (83%) and 79/127 (62%) carcinomas, respectively. Patients with low DNMT1 expression demonstrated a significantly better histopathological/clinical response (P=0.03/P=0.008) and OS (P(log-rank)=0.001). In vitro, knockdown of DNMT1 caused an increased chemosensitivity towards cisplatin. Combined treatment with cisplatin and DAC showed a synergistic effect leading to increased cytotoxicity in the cisplatin-resistant cell line AGS.
  
  
  CONCLUSIONS
  Low DNMT1 expression defines a subgroup of GC patients with better outcomes following platinum/5FU-based neoadjuvant chemotherapy. In vitro data support a functional relationship between DNMT1 and cisplatin sensitivity. Besides its potential use as a predictive biomarker, DNMT1 may represent a promising target for alternative therapeutic strategies for a subset of GC patients.
authors: Institute of Pathology, Technische Universität München, Trogerstr. 18, 81675 München, Germany.
authors: Kathrin
authors: K
authors: Mutze
authors: Rupert
authors: R
authors: Langer
authors: Felix
authors: F
authors: Schumacher
authors: Karen
authors: K
authors: Becker
authors: Katja
authors: K
authors: Ott
authors: Alexander
authors: A
authors: Novotny
authors: Alexander
authors: A
authors: Hapfelmeier
authors: Heinz
authors: H
authors: Höfler
authors: Gisela
authors: G
authors: Keller
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D014408:Biomarkers, Tumor / Q000032:analysis*; D002277:Carcinoma / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000032:analysis*; D019175:DNA Methylation; D000077209:Decitabine; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000379:methods; D015999:Multivariate Analysis; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D016896:Treatment Outcome; D014410:Tumor Stem Cell Assay; D000097584:DNA Methyltransferase 3B
chemical_list: D001374:Azacitidine; D014408:Biomarkers, Tumor; D002945:Cisplatin; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000077209:Decitabine; D000097584:DNA Methyltransferase 3B; C000619380:DNMT1 protein, human