title: Single nucleotide polymorphisms of the EpCAM-coding gene TACSTD1 in patients with ovarian cancer and their potential translational aspects.
abstract: OBJECTIVE
  EpCAM is overexpressed in many neoplasms including ovarian cancer. We screened the EpCAM-coding gene TACSTD1 for single nucleotide polymorphisms (SNPs), which could alter ovarian cancer risk, impact upon disease progression, or alter binding of the therapeutic EpCAM-binding antibody, catumaxomab.
  
  
  METHODS
  DNA fragments of 10 healthy volunteers were analyzed to identify SNPs. Subsequently, DNA of ovarian cancer patients (n = 117) and age-matched healthy controls (n = 115) was genotyped by restriction fragment length polymorphism and pyrosequencing. TACSTD1 genotypes 4461T>C were cloned into a gene expression vector; Hek293 cells were subsequently used for stable transfection. FACS analysis of the transfected Hek293 cells was conducted with HO-3-the EpCAM binding site of catumaxomab-to determine antibody binding.
  
  
  RESULTS
  One SNP was detected in exon 3 (4461T>C; rs1126497), resulting in an amino acid exchange at position 115 (Met115Thr). Another polymorphism was found in the 3'UTR (17225A>G; rs1421). Genotyping of patients and controls for these SNPs did not reveal significant differences in genotype distribution. Regarding 17225A>G, the homozygous AA-genotype was associated with diminished progression-free survival (PFS; p = 0.032). Overall survival, FIGO-stage, grading, and age did not differ significantly between genotypes. FACS analysis of transfected Hek293 cells overexpressing EpCAM 115Met/Thr showed binding of HO-3 to both proteins.
  
  
  CONCLUSIONS
  The AA-genotype of 17225A>G seems to be associated with diminished PFS in ovarian cancer patients. The amino acid exchange resulting from 4461T>C does not appear to alter binding of HO-3, suggesting that treatment with catumaxomab can be offered to patients regardless of their TACSTD1-genotype.
authors.affiliation: Institute of Pharmacogenetics, Medical Faculty, University of Duisburg-Essen, Essen, Germany. Martin.heubner@uk-essen.de.|Department of Obstetrics and Gynaecology, Medical Faculty, Clinic of Obstetrics and Gynaecology, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147, Essen, Germany. Martin.heubner@uk-essen.de.|DKTK Deutsches Konsortium für translationale Krebsforschung, Partnerstandorte Essen/Düsseldorf und, Dresden, Germany. Martin.heubner@uk-essen.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Heubner
authors.affiliation: Department of Obstetrics and Gynaecology, Medical Faculty, University Hospital Dresden, University of Dresden, Dresden, Germany.|DKTK Deutsches Konsortium für translationale Krebsforschung, Partnerstandorte Essen/Düsseldorf und, Dresden, Germany.
authors.forename: Pauline
authors.initials: P
authors.lastname: Wimberger
authors.affiliation: Department of Obstetrics and Gynaecology, Medical Faculty, Clinic of Obstetrics and Gynaecology, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147, Essen, Germany.|DKTK Deutsches Konsortium für translationale Krebsforschung, Partnerstandorte Essen/Düsseldorf und, Dresden, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Kasimir-Bauer
authors.affiliation: Institute of Anatomy, Medical Faculty, University of Duisburg-Essen, Essen, Germany.
authors.forename: Bernhard B
authors.initials: BB
authors.lastname: Singer
authors.affiliation: TRION Research GmbH, Martinsried, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Ruf
authors.affiliation: Department of Obstetrics and Gynaecology, Medical Faculty, Clinic of Obstetrics and Gynaecology, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147, Essen, Germany.|DKTK Deutsches Konsortium für translationale Krebsforschung, Partnerstandorte Essen/Düsseldorf und, Dresden, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Kimmig
authors.affiliation: Institute of Pharmacogenetics, Medical Faculty, University of Duisburg-Essen, Essen, Germany.|DKTK Deutsches Konsortium für translationale Krebsforschung, Partnerstandorte Essen/Düsseldorf und, Dresden, Germany.
authors.forename: Winfried
authors.initials: W
authors.lastname: Siffert
mesh_terms: D000328:Adult; D000368:Aged; D018033:Antibodies, Bispecific / Q000235:genetics*; D000951:Antigens, Neoplasm / Q000235:genetics*; D016022:Case-Control Studies; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use; D000071858:Epithelial Cell Adhesion Molecule; D005260:Female; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D008875:Middle Aged; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000235:genetics*; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D014162:Transfection
chemical_list: D018033:Antibodies, Bispecific; D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; C499380:TACSTD2 protein, human; C522419:catumaxomab
keywords: Catumaxomab; EpCAM; Ovarian cancer; Polymorphism; SNP; TACSTD1