title: An integrated clinical-genomics approach identifies a candidate multi-analyte blood test for serous ovarian carcinoma.
abstract: OBJECTIVE
  Cancer of the ovary confers the worst prognosis among women with gynecologic malignancies, underscoring the need to develop new biomarkers for detection of early disease, particularly those that can be readily monitored in the blood.
  
  
  METHODS
  We developed an algorithm to identify secreted proteins encoded among approximately 22,500 genes on commercial oligonucleotide arrays and applied it to gene expression profiles of 67 stage I to IV serous papillary carcinomas and 9 crudely enriched normal ovarian tissues, to identify putative diagnostic markers. ELISAs were used to validate increased levels of secreted proteins in patient sera encoded by genes with differentially high expression.
  
  
  RESULTS
  We identified 275 genes predicted to encode secreted proteins with increased/decreased expression in ovarian cancers (<0.5- or >2-fold, P < 0.001). The serum levels of four of these proteins (matrix metalloproteinase-7, osteopontin, secretory leukoprotease inhibitor, and kallikrein 10) were significantly elevated in a series of 67 independent patients with serous ovarian carcinomas compared with 67 healthy controls (P < 0.001, Wilcoxon rank sum test). Optimized support vector machine classifiers with as few as two of these markers (osteopontin or kallikrein 10/matrix metalloproteinase-7) in combination with CA-125 yielded sensitivity and specificity values ranging from 96% to 98.7% and 99.7% to 100%, respectively, with the ability to discern early-stage disease from normal, healthy controls.
  
  
  CONCLUSIONS
  Our data suggest that this assay combination warrants further investigation as a multi-analyte diagnostic test for serous ovarian adenocarcinoma.
authors.affiliation: Department of Gynecology and Obstetrics, University Hospital Schleswig-Holstein, Kiel, Germany. imeinhold@email.uni-kiel.de
authors.forename: Ivo
authors.initials: I
authors.lastname: Meinhold-Heerlein
authors.forename: Dirk
authors.initials: D
authors.lastname: Bauerschlag
authors.forename: Yingyao
authors.initials: Y
authors.lastname: Zhou
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Sapinoso
authors.forename: Keith
authors.initials: K
authors.lastname: Ching
authors.forename: Henry
authors.initials: H
authors.lastname: Frierson
authors.forename: Karen
authors.initials: K
authors.lastname: Bräutigam
authors.forename: Jalid
authors.initials: J
authors.lastname: Sehouli
authors.forename: Elmar
authors.initials: E
authors.lastname: Stickeler
authors.forename: Dominique
authors.initials: D
authors.lastname: Könsgen
authors.forename: Felix
authors.initials: F
authors.lastname: Hilpert
authors.forename: Constantin S
authors.initials: CS
authors.lastname: von Kaisenberg
authors.forename: Jacobus
authors.initials: J
authors.lastname: Pfisterer
authors.forename: Thomas
authors.initials: T
authors.lastname: Bauknecht
authors.forename: Walter
authors.initials: W
authors.lastname: Jonat
authors.forename: Norbert
authors.initials: N
authors.lastname: Arnold
authors.forename: Garret M
authors.initials: GM
authors.lastname: Hampton
mesh_terms: D000465:Algorithms; D002277:Carcinoma / Q000097:blood / Q000175:diagnosis* / Q000235:genetics*; D016000:Cluster Analysis; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics / Q000379:methods*; D006801:Humans; D008403:Mass Screening / Q000379:methods; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000097:blood* / Q000175:diagnosis / Q000235:genetics*; D011379:Prognosis