Proteogenomic analysis of enriched HGSOC tumor epithelium identifies prognostic signatures and therapeutic vulnerabilities

Abstract

'Andrew McPherson' 'Seongmin Choi' 'Dale W. Garsed' 'Ahwan Pandey' 'Chunqiao Tian' 'Brian L. Hood' 'Kelly A. Conrads' 'Pang-ning Teng' 'Julie Oliver' 'Glenn Gist' 'Dave Mitchell' 'Tracy J. Litzi' 'Christopher M. Tarney' 'Barbara A. Crothers' 'Paulette Mhawech-Fauceglia' 'Clifton L. Dalgard' 'Matthew D. Wilkerson' 'Mariaelena Pierobon' 'Emanuel F. Petricoin' 'Chunhua Yan' 'Daoud Meerzaman' 'Clara Bodelon' 'Nicolas Wentzensen' 'Jerry S. H. Lee' '' 'David G. Huntsman' 'Sohrab Shah' 'Craig D. Shriver' 'Neil T. Phippen' 'Kathleen M. Darcy' 'David D. L. Bowtell' 'Thomas P. Conrads' 'G. Larry Maxwell'] We performed a deep proteogenomic analysis of bulk tumor and laser microdissection enriched tumor cell populations from high-grade serous ovarian cancer (HGSOC) tissue specimens spanning a broad spectrum of purity. We identified patients with longer progression-free survival had increased immune-related signatures and validated proteins correlating with tumor-infiltrating lymphocytes in 65 tumors from an independent cohort of HGSOC patients, as well as with overall survival in an additional 126 HGSOC patient cohort. We identified that homologous recombination deficient (HRD) tumors are enriched in pathways associated with metabolism and oxidative phosphorylation that we validated in independent patient cohorts. We further identified that polycomb complex protein BMI-1 is elevated in HR proficient (HRP) tumors, that elevated BMI-1 correlates with poor overall survival in HRP but not HRD HGSOC patients, and that HRP HGSOC cells are uniquely sensitive to BMI-1 inhibition.