title: Expression and clinical role of chemoresponse-associated genes in ovarian serous carcinoma.
abstract: OBJECTIVE
  To validate our earlier observation that 11 chemoresistance-associated mRNAs are molecular markers of poor overall survival in ovarian serous carcinoma.
  
  
  METHODS
  Ovarian serous carcinomas (n=112) and solid metastases (n=63; total=175) were analyzed for mRNA expression of APC, BAG3, EGFR, S100A10, ITGAE, MAPK3, TAP1, BNIP3, MMP9, FASLG and GPX3 using quantitative real-time PCR. mRNA expression was studied for association with clinicopathologic parameters and survival. Tumor heterogeneity was assessed in 20 cases with >1 specimen per patient. APC, BAG3, S100A10 and ERK1 protein expression by immunohistochemistry was analyzed in 58 specimens (38 primary carcinomas, 20 metastases).
  
  
  RESULTS
  BAG3 (p=0.013), TAP1 (p=0.014), BNIP3 (p<0.001) and MMP9 (p=0.036) were overexpressed in primary tumors, whereas S100A10 (p=0.027) and FASLG (p=0.006) were overexpressed in metastases. Analysis of patient-matched primary carcinomas and metastases showed overexpression of APC (p=0.022), MAPK3 (p=0.002) and BNIP3 (p=0.004) in the former. In primary carcinomas, higher APC (p=0.003) and MAPK3 (p=0.005) levels were related to less favorable chemoresponse. Higher S100A10 (p=0.029) and MAPK3 (p=0.041) levels were related to primary chemoresistance. Higher BAG3 (p=0.026) and APC (p=0.046) levels in primary carcinomas were significantly related to poor overall survival in univariate, though not in multivariate survival analysis. S100A10 protein expression was related to poor chemoresponse (p=0.002) and shorter overall (p=0.005) and progression-free (p<0.001) survival, the latter finding retained in multivariate analysis (p=0.035).
  
  
  CONCLUSIONS
  Our data provide evidence of heterogeneity in ovarian serous carcinoma and identify APC, MAPK3, BAG3 and S100A10 as potential biomarkers of poor chemotherapy response and/or poor outcome in this cancer.
authors.affiliation: Department of Pathology, Oslo University Hospital, Norwegian Radium Hospital, N-0310 Oslo, Norway.
authors.forename: Dag Andre
authors.initials: DA
authors.lastname: Nymoen
authors.affiliation: Department of Oncology, Oslo University Hospital, Norwegian Radium Hospital, N-0310 Oslo, Norway.
authors.forename: Thea E
authors.initials: TE
authors.lastname: Hetland Falkenthal
authors.affiliation: Department of Pathology, Oslo University Hospital, Norwegian Radium Hospital, N-0310 Oslo, Norway.
authors.forename: Arild
authors.initials: A
authors.lastname: Holth
authors.affiliation: Bioinformatics Institute, A*STAR, Singapore.
authors.forename: Ghim Siong
authors.initials: GS
authors.lastname: Ow
authors.affiliation: Bioinformatics Institute, A*STAR, Singapore.
authors.forename: Anna V
authors.initials: AV
authors.lastname: Ivshina
authors.affiliation: Department of Gynecologic Oncology, Oslo University Hospital, Norwegian Radium Hospital, N-0310 Oslo, Norway; University of Oslo, Faculty of Medicine, Institute of Clinical Medicine, N-0310 Oslo, Norway.
authors.forename: Claes G
authors.initials: CG
authors.lastname: Tropé
authors.affiliation: Bioinformatics Institute, A*STAR, Singapore; School for Integrative Science and Engineering, National University of Singapore, Singapore; School of Computing Engineering, Nanyang Technological University, Singapore.
authors.forename: Vladimir A
authors.initials: VA
authors.lastname: Kuznetsov
authors.affiliation: University of Oslo, Faculty of Medicine, Institute of Clinical Medicine, N-0310 Oslo, Norway; Department of Obstetrics and Gynecology, Ulleval University Hospital, N-0407 Oslo, Norway.
authors.forename: Anne Cathrine
authors.initials: AC
authors.lastname: Staff
authors.affiliation: Department of Pathology, Oslo University Hospital, Norwegian Radium Hospital, N-0310 Oslo, Norway; University of Oslo, Faculty of Medicine, Institute of Clinical Medicine, N-0310 Oslo, Norway. Electronic address: bend@medisin.uio.no.
authors.forename: Ben
authors.initials: B
authors.lastname: Davidson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics; D025601:Adenomatous Polyposis Coli Protein / Q000096:biosynthesis / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017306:Annexin A2 / Q000096:biosynthesis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics*; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006801:Humans; D008875:Middle Aged; D048052:Mitogen-Activated Protein Kinase 3 / Q000096:biosynthesis / Q000235:genetics; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D009418:S100 Proteins / Q000096:biosynthesis / Q000235:genetics; D000099248:S100 Calcium Binding Protein A10
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D025601:Adenomatous Polyposis Coli Protein; D017306:Annexin A2; D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor; D048052:Mitogen-Activated Protein Kinase 3; D012333:RNA, Messenger; D009418:S100 Proteins; D000099248:S100 Calcium Binding Protein A10; C555337:APC protein, human; C414431:BAG3 protein, human
keywords: Chemotherapy response; Metastases; Ovarian serous carcinoma; Quantitative PCR; Survival; Tumor heterogeneity