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

Nicholas W Bateman; Tamara Abulez; Anthony R Soltis; 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; APOLLO Research Network; David G Huntsman; Sohrab Shah; Craig D Shriver; Neil T Phippen; Kathleen M Darcy; David D L Bowtell; Thomas P Conrads; G Larry Maxwell

doi:10.1038/s41698-024-00519-8

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

NPJ Precis Oncol. 2024 Mar 13;8(1):68. doi: 10.1038/s41698-024-00519-8.

Authors

Nicholas W Bateman^#^{1

2

3}, Tamara Abulez^{4

5}, Anthony R Soltis⁶, Andrew McPherson⁷, Seongmin Choi⁷, Dale W Garsed^{8

9}, Ahwan Pandey⁸, Chunqiao Tian^{4

5}, Brian L Hood^{4

5}, Kelly A Conrads^{4

5}, Pang-Ning Teng^{4

5}, Julie Oliver^{4

5}, Glenn Gist^{4

5}, Dave Mitchell^{4

5}, Tracy J Litzi^{4

5}, Christopher M Tarney⁴, Barbara A Crothers¹⁰, Paulette Mhawech-Fauceglia¹¹, Clifton L Dalgard⁶, Matthew D Wilkerson⁶, Mariaelena Pierobon¹², Emanuel F Petricoin¹², Chunhua Yan¹³, Daoud Meerzaman¹³, Clara Bodelon¹⁴, Nicolas Wentzensen¹⁴, Jerry S H Lee¹⁵; APOLLO Research Network; David G Huntsman¹⁶, Sohrab Shah⁷, Craig D Shriver¹⁷, Neil T Phippen⁴, Kathleen M Darcy^{4

5

17}, David D L Bowtell^{8

9}, Thomas P Conrads^#^{18

19

20}, G Larry Maxwell^#^{21

22

23}

Affiliations

¹ Gynecologic Cancer Center of Excellence, Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA. batemann@whirc.org.
² The Henry M. Jackson Foundation for the Advancement of Military Medicine Inc, Bethesda, MD, USA. batemann@whirc.org.
³ The John P. Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University and Walter Reed National Military Medical Center, Bethesda, MD, USA. batemann@whirc.org.
⁴ Gynecologic Cancer Center of Excellence, Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
⁵ The Henry M. Jackson Foundation for the Advancement of Military Medicine Inc, Bethesda, MD, USA.
⁶ The American Genome Center, Collaborative Health Initiative Research Program, Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
⁷ Department of Computational Oncology, Memorial Sloan Kettering Cancer Center, Manhattan, NY, USA.
⁸ Peter MacCallum Cancer Centre, Parkville, Melbourne, Victoria, Australia.
⁹ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.
¹⁰ The Joint Pathology Center, Defense Health Agency, National Capital Region Medical Directorate, Silver Spring, MD, USA.
¹¹ Department of Anatomic Pathology, Division of Gynecologic Pathology, University of Southern California, Los Angeles, CA, USA.
¹² Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA.
¹³ Center for Biomedical Informatics and Information Technology, National Cancer Institute, Rockville, MD, USA.
¹⁴ Division of Cancer Epidemiology and Genetics National Cancer Institute, Rockville, MD, USA.
¹⁵ Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA, USA.
¹⁶ Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, British Columbia, Canada.
¹⁷ The John P. Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University and Walter Reed National Military Medical Center, Bethesda, MD, USA.
¹⁸ Gynecologic Cancer Center of Excellence, Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA. conrads@whirc.org.
¹⁹ The John P. Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University and Walter Reed National Military Medical Center, Bethesda, MD, USA. conrads@whirc.org.
²⁰ Women's Health Integrated Research Center, Women's Service Line, Inova Health System, Falls Church, VA, USA. conrads@whirc.org.
²¹ Gynecologic Cancer Center of Excellence, Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA. george.maxwell@inova.org.
²² The John P. Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University and Walter Reed National Military Medical Center, Bethesda, MD, USA. george.maxwell@inova.org.
²³ Women's Health Integrated Research Center, Women's Service Line, Inova Health System, Falls Church, VA, USA. george.maxwell@inova.org.

^# Contributed equally.

Abstract

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.

Grants and funding

P30 CA008748/CA/NCI NIH HHS/United States