Discovery and verification of early detection ovarian cancer plasma/serum biomarkers.
1. Candidate discovery via
a. LC/MS in ovarian cyst fluid
b. LC/MS in vibratome sliced fresh tissue (fallopian tube vs ovarian cancer)
c. LC/MS in conditioned media from phenocopy model fallopian tube system
d. Affy arrays in fallopian/ovarian tissue filtered by secretome
2. Integrated prioritization of candidates for verification by systems biology/pathway analysis
3. Verification of 50 candidates in plasma from 50 cases & 50 benign adnexal masses, and in longitudinal plasma from ovarian cancer screening trial
4. Longitudinal change-point analysis to determine candidates with earliest significant rise above baseline
Phase 1 will consist of the proteomic analysis of proximal fluids (ovarian cyst fluid, conditioned media from FTE or ex-vivo phenocopy system if needed) and genomic analysis of ovarian/fallopian tube tissue and will occur during years 0-2.5, and produce a list of candidate discovery biomarkers. The ovarian cyst fluid follows the PRoBE design since at time the fluid is obtained the pathological diagnosis has not been made, and
therefore the design will be a nested case-control one. However, the conditioned media will be from known cases and control subjects, so will not be PRoBE compliant – as there is no feasible way to achieve this goal in this setting. Quantitative criteria for phase 1 genomic and proteomic over-expression are that the ratio exceeds 5 with a p-value < 0.001 assessed by the permutation test (false discovery rate FDR < 10%).
Phase 2 will consist of the AIMS experiments to determine which discovery candidates are detectable in multiple pools of plasma, and SISCAPA-MRM experiments in plasma biospecimens obtained prior to surgery in patients with pelvic masses, to determine which candidates differentiate malignant from benign disease.
The pools of plasma will be from the same set of patients as from which the cyst fluid was obtained, while the plasma samples will be from the same patients and patients with a pelvic mass but without a cyst, which is the case for the majority of patients with a pelvic mass. Therefore the plasma specimens will
be from a patient set which is a super-set of the cyst fluid patients. SISCAPA-MRM over-expression are that the 95% probability intervals for sensitivity at 98% specificity exceed 5%, that is, there is evidence that there is at least 5% sensitivity
contributed to ovarian cancer detection by a candidate biomarker before going on to phase 3.
Phase 3 will consist of SISCAPA-MRM experiments to measure the best 50 candidates in longitudinal samples from a pilot screening trial, and will occur from years 3-5. Screening samples automatically comply with the PRoBE design as they are collected prospectively before diagnosis is known and will be evaluated without knowledge of their case/control status. The quantitative criterion for the next phase is that the longitudinal algorithm for a given candidate provides a sensitivity of at least 10% at 1-2 years prior to detection at 98% specificity.
There are currently no biomarkers annotated for this protocol.
No datasets are currently associated with this protocol.
The National Cancer Institute's Division of Cancer Prevention has released a new funding opportunity to solicit organ-specific applications for Biomarker Developmental Laboratories (BDLs), one of the four scientific units of the recently funded Early Detection Research Network (EDRN). The EDRN is a national infrastructure funded to discover, develop, and validate biomarkers for risk assessment, detection, and molecular diagnosis and prognosis of early cancer. BDLs are responsible for the discovery, development, characterization, and testing of new, or the refinement of existing, biomarkers and biomarker assays for risk assessment, detection, and molecular diagnosis and prognosis of cancers.
The existing BDLs are primarily focused on ovary and gastrointestinal cancers. The proposed BDLs (to be supported under this funding opportunity) should be focused on one or more of the following cancers: breast, prostate and other genitourinary organs, or lung. In addition, cancers with rapidly rising incidence rates, e.g., endometrial, hepatocellular, kidney, thyroid, oropharyngeal cancers, and/or cancers with unique etiology, e.g., mesothelioma, will be considered.
The newly funded units of the Early Detection Research Network will be announced later in April. Successful applicants have already been notified. Those researchers who were not successful during the last round of applications are encouraged to apply to this opportunity.