A combined blood based gene expression and plasma protein abundance signature for diagnosis of epithelial ovarian cancer--a study of the OVCAD consortium

BMC Cancer. 2013 Apr 3;13:178. doi: 10.1186/1471-2407-13-178.

Abstract

Background: The immune system is a key player in fighting cancer. Thus, we sought to identify a molecular 'immune response signature' indicating the presence of epithelial ovarian cancer (EOC) and to combine this with a serum protein biomarker panel to increase the specificity and sensitivity for earlier detection of EOC.

Methods: Comparing the expression of 32,000 genes in a leukocytes fraction from 44 EOC patients and 19 controls, three uncorrelated shrunken centroid models were selected, comprised of 7, 14, and 6 genes. A second selection step using RT-qPCR data and significance analysis of microarrays yielded 13 genes (AP2A1, B4GALT1, C1orf63, CCR2, CFP, DIS3, NEAT1, NOXA1, OSM, PAPOLG, PRIC285, ZNF419, and BC037918) which were finally used in 343 samples (90 healthy, six cystadenoma, eight low malignant potential tumor, 19 FIGO I/II, and 220 FIGO III/IV EOC patients). Using new 65 controls and 224 EOC patients (thereof 14 FIGO I/II) the abundances of six plasma proteins (MIF, prolactin, CA125, leptin, osteopondin, and IGF2) was determined and used in combination with the expression values from the 13 genes for diagnosis of EOC.

Results: Combined diagnostic models using either each five gene expression and plasma protein abundance values or 13 gene expression and six plasma protein abundance values can discriminate controls from patients with EOC with Receiver Operator Characteristics Area Under the Curve values of 0.998 and bootstrap .632+ validated classification errors of 3.1% and 2.8%, respectively. The sensitivities were 97.8% and 95.6%, respectively, at a set specificity of 99.6%.

Conclusions: The combination of gene expression and plasma protein based blood derived biomarkers in one diagnostic model increases the sensitivity and the specificity significantly. Such a diagnostic test may allow earlier diagnosis of epithelial ovarian cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Analysis of Variance
  • Area Under Curve
  • Biomarkers, Tumor / blood*
  • Blood Proteins / genetics*
  • CA-125 Antigen / blood
  • Carcinoma, Ovarian Epithelial
  • Case-Control Studies
  • Cystadenoma / blood*
  • Cystadenoma / genetics*
  • Female
  • Gene Expression Profiling*
  • Humans
  • Insulin-Like Growth Factor II / metabolism
  • Intramolecular Oxidoreductases / blood
  • Leptin / blood
  • Macrophage Migration-Inhibitory Factors / blood
  • Membrane Proteins / blood
  • Middle Aged
  • Neoplasms, Glandular and Epithelial / blood*
  • Neoplasms, Glandular and Epithelial / genetics*
  • Neoplasms, Glandular and Epithelial / pathology
  • Oligonucleotide Array Sequence Analysis
  • Osteopontin / blood
  • Ovarian Neoplasms / blood*
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / pathology
  • Prolactin / blood
  • ROC Curve
  • Retrospective Studies
  • Young Adult

Substances

  • Biomarkers, Tumor
  • Blood Proteins
  • CA-125 Antigen
  • IGF2 protein, human
  • Leptin
  • MUC16 protein, human
  • Macrophage Migration-Inhibitory Factors
  • Membrane Proteins
  • Osteopontin
  • Insulin-Like Growth Factor II
  • Prolactin
  • Intramolecular Oxidoreductases
  • MIF protein, human