An integrated clinical-genomics approach identifies a candidate multi-analyte blood test for serous ovarian carcinoma.
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.
Meinhold-Heerlein
Ivo
I
Department of Gynecology and Obstetrics, University Hospital Schleswig-Holstein, Kiel, Germany. imeinhold@email.uni-kiel.de
Bauerschlag
Dirk
D
Zhou
Yingyao
Y
Sapinoso
Lisa M
LM
Ching
Keith
K
Frierson
Henry
H
Bräutigam
Karen
K
Sehouli
Jalid
J
Stickeler
Elmar
E
Könsgen
Dominique
D
Hilpert
Felix
F
von Kaisenberg
Constantin S
CS
Pfisterer
Jacobus
J
Bauknecht
Thomas
T
Jonat
Walter
W
Arnold
Norbert
N
Hampton
Garret M
GM
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