Project 3: Identifying novel biomarkers of ovarian cancer with application to high risk women undergoing risk reducing salpingo oophorectomy

Specific Aims

• Prospectively enroll a large cohort of women at high inherited risk for ovarian cancer who are planning risk reducing salpingo-oophorectomy (RRSO) and accumulate a biorepository of pre-operative and post-operative serum, plasma, and urine specimens. Centralized gynecologic pathology review will identify three sub-groups of women: (i) with occult ovarian cancers, (ii) other ovarian neoplasias, and  (iii) no ovarian neoplasias (controls).
• Identify novel serum, plasma, and urine biomarkers and their patterns for detecting low volume early stage ovarian cancer and other ovarian neoplasias. Samples collected in Aim 1 will be analyzed for combinations of putative ovarian cancer markers by mass spectrometry and 2D differential gel electrophoresis (2D-DIGE). Non-linear classification analyses will identify the optimal combinations of six putative markers for separating samples between the sub-groups.
• The proteins and peptides representing the six peaks/spots in the optimal pattern will be identified through LC-MS/MS, and monoclonal antibodies developed against these proteins and peptides. Immunoassays will be developed from the monoclonal antibodies, which will substantially reduce biomarker quantitation variability. This process will thereby increase separation between the sub-groups, and yield repeatable high precision assays. Biomarkers will be remeasured by these immunoassays in samples from the three sub-groups, and non-linear classification analyses will quantify immunoassay based optimal biomarker classification patterns and their operating characteristics.

Publications

Greene MH, Piedmonte M, Alberts D, Gail M, Hensley M, Miner Z, Mai PL, Loud J, Rodriguez G, Basil J, et al. "A prospective study of risk-reducing salpingo-oophorectomy and longitudinal CA-125 screening among women at increased genetic risk of ovarian cancer: design and baseline characteristics: a gynecologic oncology group study." Cancer Epidemiol Biomarkers Prev 2008; 17(3):pg:594-604. PMCID: 18349277

Lee Y, Miron A, Drapkin R, Nucci MR, Medeiros F, Saleemuddin A, Garber J, Birch C, Mou H, Gordon RW, et al. "A candidate precursor to serous carcinoma that originates in the distal fallopian tube." J Pathol 2007; 211(1):pg:26-35. PMCID: 17117391++

Menon, U., et al., Innovative approaches to recruitment to multicentre trials - Descriptive Study. British Medical Journal, in press.

Moore, R.C., et al., A novel multiple marker bioassay utilizing HE4 and CA125 for the prediction of ovarian cancer in patients with a pelvic mass. Gynecologic Oncology, in press

Moore RG, Brown AK, Miller MC, Skates S, Allard WJ, Verch T, Steinhoff M, Messerlian G, DiSilvestro P, Granai CO, et al. "The use of multiple novel tumor biomarkers for the detection of ovarian carcinoma in patients with a pelvic mass." Gynecol Oncol 2008; 108(2):pg:402-408. PMCID: 18061248

Ye B, Skates S, Mok SC, Horick NK, Rosenberg HF, Vitonis A, Edwards D, Sluss P, Han WK, Berkowitz RS, et al. "Proteomic-based discovery and characterization of glycosylated eosinophil-derived neurotoxin and COOH-terminal osteopontin fragments for ovarian cancer in urine." Clin Cancer Res 2006; 12(2):pg:432-441. PMCID: 16428483

Comments: For the continuation application, Dr. Skates will take advantage of new developments in mass spectrographic profiling of blood proteins at the Broad Institute together with unique specimen sets that we believe will culminate in testing of screening biomarkers in the specimens from the largest trail of screening in the world being conducted in the United Kingdom.

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