title: Loss of BRCA1 expression leads to worse survival in patients with gastric carcinoma.
abstract: OBJECTIVE
  To investigate the expression deficiency of key molecular markers in the homologous recombination pathway.
  
  
  METHODS
  Expression loss of breast cancer type 1 susceptibility protein (BRCA1), ataxia telangiectasia mutated (ATM), ATM-Rad3-related (ATR), mediator of DNA damage checkpoint protein 1 (MDC1) and meiotic recombination 11 (Mre11) were correlated with their clinicopathological parameters in gastric cancer (GC). One hundred and twenty treatment-naive GC samples were formalin-fixed and paraffin-embedded into tissue blocks. Two representative cores from each block were extracted and constructed into tissue microarrays. Expression levels of BRCA1, ATM, ATR, MDC1 and Mre11 were determined using immunohistochemical analysis, and correlated with clinical parameters, including age, gender, Lauren subtype, tumor grades, clinical stage and overall survival.
  
  
  RESULTS
  Expression loss of BRCA1, ATM, ATR, MDC1, and Mre11 was found in 21.4%, 20.2%, 21.0%, 11.1% and 4.6%, respectively, of interpretable cases. BRCA1 loss was significantly associated with patients of diffused subtype (intestinal vs diffused, 8.2% vs 31.7%, P = 0.001), higher tumor grade (I/II vs III, 10.7% vs 20.5; I/II vs IV, 10.7% vs 54.5%, P = 0.047) and advanced clinical stage (I/II vs III, 12.9% vs 16.9%; I/II vs IV, 12.9% vs 45.5%, P = 0.006). MDC1 loss was significantly associated with patients of diffused subtype (intestinal vs diffused, 0% vs 19.7%, P = 0.001) and higher tumor grade (I/II vs III, 0% vs 12%; I/II vs IV, 0% vs 30.8%, P = 0.012). In addition, the survival time of the patients with expression loss of BRCA1 was significantly shorter than those with positive expression of BRCA1 (2-year survival rate, 32.4% vs 62.8%, P = 0.015). No correlations were found between clinicopathological parameters and expression loss of ATM, ATR and Mre11.
  
  
  CONCLUSIONS
  Our results support the hypothesis that homologous recombination deficiency plays an important role in the progression of gastric carcinoma. Loss of expression of BRCA1 and MDC1 may serve as predictive factors in tumor development or progression in GC patients.
authors.affiliation: Department of General Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China.
authors.forename: Zi-Zhen
authors.initials: ZZ
authors.lastname: Zhang
authors.forename: Yuan Jie Charles
authors.initials: YJ
authors.lastname: Liu
authors.forename: Xiao-Lu
authors.initials: XL
authors.lastname: Yin
authors.forename: Ping
authors.initials: P
authors.lastname: Zhan
authors.forename: Yi
authors.initials: Y
authors.lastname: Gu
authors.forename: Xing-Zhi
authors.initials: XZ
authors.lastname: Ni
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D019313:BRCA1 Protein / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002681:China / Q000453:epidemiology; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D019398:Genes, BRCA1; D059765:Homologous Recombination; D006801:Humans; D000076228:MRE11 Homologue Protein; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000378:metabolism; D013270:Stomach / Q000473:pathology; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D015534:Trans-Activators / Q000378:metabolism; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019313:BRCA1 Protein; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C413163:MDC1 protein, human; C121766:MRE11 protein, human; D009687:Nuclear Proteins; D015534:Trans-Activators; D064007:Ataxia Telangiectasia Mutated Proteins; D000076228:MRE11 Homologue Protein
keywords: Ataxia telangiectasia mutated; Ataxia telangiectasia mutated-Rad3-related; Breast cancer type 1 susceptibility protein; Gastric cancer; Homologous recombination deficiency; Mediator of DNA damage checkpoint protein 1