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39 Interim analysis of ovarian cancer by the us national cancer moonshot’s tri-federal (DOD/NCI/VA) applied proteogenomic organizational learning and outcomes (APOLLO) research network
  1. GL Maxwell1,2,
  2. NW Bateman2,3,
  3. AR Soltis4,
  4. G Wang3,
  5. CL Dalgard4,
  6. EF Petricoin5,
  7. CM Tarney6,
  8. C Rojas6,
  9. L Havrilesky7,
  10. DE Cohn8,
  11. JM Wells9,
  12. H Hu10,
  13. CA Hamilton1,2,
  14. CD Shriver11,
  15. M Wilkerson4,
  16. Y Casablanca2,12,
  17. K Darcy2,3 and
  18. TP Conrads1,2
  1. 1Inova Women’s Hospital- the Inova Women’s Service Line- and the Inova Schar Cancer Center, The Women’s Health Integrated Research Center and the Department of Obstetrics and Gynecology, Falls Church, USA
  2. 2The John P Murtha Cancer Center- the Uniformed Services University of the Health Sciences- and Walter Reed National Military Medical Center, Gynecologic Cancer Center of Excellence, Bethesda- MD, USA
  3. 3The Henry M. Jackson Foundation for the Advancement of Military Medicine, Gynecologic Cancer Center of Excellence, Bethesda- MD, USA
  4. 4Uniformed Services University of the Health Sciences, The American Genome Center, Bethesda- MD, USA
  5. 5George Mason University, Applied Center for Proteogenomics, Manassas- VA, USA
  6. 6Uniformed Services University of the Health Sciences and Walter Reed National Military Medical Center, Division of Gynecologic Oncology, Bethesda- MD, USA
  7. 7Duke University Medical Center, Division of Gynecologic Oncology, Durham- NC, USA
  8. 8The James Comprehesive Cancer Center and Ohio State University, Division of Gynecologic Oncology, Columbus- OH, USA
  9. 9Walter Reed National Military Medical Center, Department of Pathology, Bethesda- MD, USA
  10. 10Chan Soon-Shiong Institute of Molecular Medicine, Department of Bioinformatics, Windber- PA, USA
  11. 11Uniformed Services University of the Health Sciences, John P Murtha Cancer Center, Bethesda- MD, USA
  12. 12Walter Reed National Military Medical Center, Division of Gynecologic Oncology, Bethesda- MD, USA


Objectives Although studies including TCGA have selected for pure tumors to enhance detection of cancer-related biomarkers, many impure tumors are associated with poor prognosis raising concerns over historical selection bias. Enrichment techniques to prep tumor micro-compartments was aligned with comprehensive proteogenomic analysis in an advanced stage high grade serous ovarian cancer (HGSOC) patient cohort to detect novel, clinically-relevant alterations.

Methods 87 fresh-frozen tumor specimens were selected from a cohort of over 630 patients to reflect a continuum of tumor purity balanced by progression and disease distribution. A whole tumor (WT) specimen and one enriched for tumor epithelium was prepared for each case using laser microdissection (LMD). Specimens were analyzed by whole genome sequencing (WGS), mRNA-seq, quantitative global/phosphoproteomics, and reverse phase protein array.

Results LMD enrichment increased median tumor purity estimated by WGS from 56% in WT to 79% (P<4e-11, MWW U test) and significantly enhanced identification of somatic single nucleotide variants (SNVs) (27%, P<3e-7) and short indels (16%, P<4e-4). Following LMD, 83% of cases characterized as mesenchymal expression subtype (C4) in WT samples were reclassified to other molecular subtypes (P<0.001). LMD tumors with an immune expression subtype (C1) had improved progression-free survival (PFS) compared with other molecular subtypes (p=0.009). Differential proteomic analyses focused on signaling alterations correlating with altered PFS, homologous recombination deficiency and immune signaling.

Conclusions These data demonstrate feasibility of cohort-level proteogenomic characterization of the tumor microenvironment and establishes a non-restrictive paradigm for patient inclusion and specimen prep in support of the prospective mission-scale analyses associated with APOLLO.

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