title: Differential effect of MMSET mRNA levels on survival to first-line FOLFOX and second-line docetaxel in gastric cancer.
abstract: BACKGROUND
  Breast cancer susceptibility gene 1 (BRCA1) expression differentially affects outcome to platinum- and taxane-based chemotherapy. Mediator of DNA damage checkpoint protein 1 (MDC1), p53-binding protein 1 (53BP1), multiple myeloma SET domain (MMSET) and ubiquitin-conjugating enzyme 9 (UBC9) are involved in DNA repair and could modify the BRCA1 predictive model.
  
  
  METHODS
  Mediator of DNA damage checkpoint protein 1, 53BP1, MMSET and UBC9 mRNA were assessed in gastric tumours from patients in whom BRCA1 levels had previously been determined.
  
  
  RESULTS
  In vitro chemosensitivity assay, MMSET levels were higher in docetaxel-sensitive samples. In a separate cohort, survival was longer in those with low MMSET (12.3 vs 8.8 months; P=0.04) or UBC9 (12.4 vs 8.8 months; P=0.01) in patients receiving only folinic acid, fluorouracil (5-FU) and oxaliplatin (FOLFOX). Conversely, among patients receiving second-line docetaxel, longer survival was associated with high MMSET (19.1 vs 13.9 months; P=0.003). Patients with high MMSET and BRCA1 attained a median survival of 36.6 months, compared with 13.9 months for those with high BRCA1 and low MMSET (P=0.003). In the multivariate analyses, low MMSET (hazard ratio (HR), 0.59; P=0.04) and low UBC9 (HR, 0.52; P=0.01) levels were markers of longer survival to first-line FOLFOX, whereas palliative surgery (HR, 2.47; P=0.005), low BRCA1 (HR, 3.17; P=0.001) and low MMSET (HR, 2.52; P=0.004) levels were markers of shorter survival to second-line docetaxel.
  
  
  CONCLUSIONS
  Breast cancer susceptibility gene 1, MMSET and UBC9 can be useful for customising chemotherapy in gastric cancer patients.
authors.affiliation: The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University, Nanjing 210008, China.
authors.forename: J
authors.initials: J
authors.lastname: Wei
authors.affiliation: Pangaea Biotech, USP Dexeus University Institute, Barcelona 08028, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Costa
authors.affiliation: The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University, Nanjing 210008, China.
authors.forename: J
authors.initials: J
authors.lastname: Shen
authors.affiliation: The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University, Nanjing 210008, China.
authors.forename: L
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Preventive Medicine and Public Health, Autonomous University of Madrid, Madrid 28049, Spain.
authors.forename: J J
authors.initials: JJ
authors.lastname: Sanchez
authors.affiliation: The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University, Nanjing 210008, China.
authors.forename: X
authors.initials: X
authors.lastname: Qian
authors.affiliation: The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University, Nanjing 210008, China.
authors.forename: X
authors.initials: X
authors.lastname: Sun
authors.affiliation: The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University, Nanjing 210008, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Zou
authors.affiliation: Pangaea Biotech, USP Dexeus University Institute, Barcelona 08028, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Gimenez-Capitan
authors.affiliation: The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University, Nanjing 210008, China.
authors.forename: G
authors.initials: G
authors.lastname: Yue
authors.affiliation: Department of General Surgery, Drum Tower Hospital, Medical School of Nanjing University, Nanjing 210008, China.
authors.forename: W
authors.initials: W
authors.lastname: Guan
authors.affiliation: 1] Pangaea Biotech, USP Dexeus University Institute, Barcelona 08028, Spain [2] Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Medical Oncology Service, Badalona 08916, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Rosell
authors.affiliation: The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University, Nanjing 210008, China.
authors.forename: B
authors.initials: B
authors.lastname: Liu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins; D000077143:Docetaxel; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D015870:Gene Expression; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D016016:Proportional Hazards Models; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D043823:Taxoids / Q000008:administration & dosage; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D000071857:Tumor Suppressor p53-Binding Protein 1; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism; D055815:Young Adult; D000098843:Ubiquitin-Conjugating Enzyme UBC9
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; C413163:MDC1 protein, human; D009687:Nuclear Proteins; D009944:Organoplatinum Compounds; D012333:RNA, Messenger; D012097:Repressor Proteins; C498301:TP53BP1 protein, human; D043823:Taxoids; D015534:Trans-Activators; D000071857:Tumor Suppressor p53-Binding Protein 1; D000077143:Docetaxel; D011495:Histone-Lysine N-Methyltransferase; C419586:NSD2 protein, human; D044763:Ubiquitin-Conjugating Enzymes; D000098843:Ubiquitin-Conjugating Enzyme UBC9; D002955:Leucovorin; D005472:Fluorouracil