Proteogenomic analysis of chemo-refractory high-grade serous ovarian cancer

Shrabanti Chowdhury; Jacob J Kennedy; Richard G Ivey; Oscar D Murillo; Noshad Hosseini; Xiaoyu Song; Francesca Petralia; Anna Calinawan; Sara R Savage; Anna B Berry; Boris Reva; Umut Ozbek; Azra Krek; Weiping Ma; Felipe da Veiga Leprevost; Jiayi Ji; Seungyeul Yoo; Chenwei Lin; Uliana J Voytovich; Yajue Huang; Sun-Hee Lee; Lindsay Bergan; Travis D Lorentzen; Mehdi Mesri; Henry Rodriguez; Andrew N Hoofnagle; Zachary T Herbert; Alexey I Nesvizhskii; Bing Zhang; Jeffrey R Whiteaker; David Fenyo; Wilson McKerrow; Joshua Wang; Stephan C Schürer; Vasileios Stathias; X Steven Chen; Mary Helen Barcellos-Hoff; Timothy K Starr; Boris J Winterhoff; Andrew C Nelson; Samuel C Mok; Scott H Kaufmann; Charles Drescher; Marcin Cieslik; Pei Wang; Michael J Birrer; Amanda G Paulovich

doi:10.1016/j.cell.2023.07.004

Proteogenomic analysis of chemo-refractory high-grade serous ovarian cancer

Cell. 2023 Aug 3;186(16):3476-3498.e35. doi: 10.1016/j.cell.2023.07.004.

Authors

Shrabanti Chowdhury¹, Jacob J Kennedy², Richard G Ivey², Oscar D Murillo², Noshad Hosseini³, Xiaoyu Song⁴, Francesca Petralia¹, Anna Calinawan¹, Sara R Savage⁵, Anna B Berry⁶, Boris Reva¹, Umut Ozbek⁷, Azra Krek¹, Weiping Ma¹, Felipe da Veiga Leprevost⁸, Jiayi Ji¹, Seungyeul Yoo⁹, Chenwei Lin², Uliana J Voytovich², Yajue Huang¹⁰, Sun-Hee Lee¹¹, Lindsay Bergan¹², Travis D Lorentzen², Mehdi Mesri¹³, Henry Rodriguez¹³, Andrew N Hoofnagle¹⁴, Zachary T Herbert¹⁵, Alexey I Nesvizhskii¹⁶, Bing Zhang⁵, Jeffrey R Whiteaker², David Fenyo¹⁷, Wilson McKerrow¹⁷, Joshua Wang¹⁷, Stephan C Schürer¹⁸, Vasileios Stathias¹⁸, X Steven Chen¹⁹, Mary Helen Barcellos-Hoff²⁰, Timothy K Starr²¹, Boris J Winterhoff²¹, Andrew C Nelson²², Samuel C Mok²³, Scott H Kaufmann¹¹, Charles Drescher¹², Marcin Cieslik²⁴, Pei Wang²⁵, Michael J Birrer²⁶, Amanda G Paulovich²⁷

Affiliations

¹ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
² Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
³ Department of Computational Medicine and Bioinformatics, Michigan Center for Translational Pathology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
⁴ Tisch Cancer Institute, Department of Population Health Science and Policy, Institute for Health Care Delivery Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁵ Lester and Sue Smith Breast Center, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
⁶ Syapse, Inc., San Francisco, CA 94115, USA.
⁷ Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁸ Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
⁹ Sema4, Inc., Stamford, CT 06902, USA.
¹⁰ Department of Laboratory Medicine & Pathology, Mayo Clinic, Rochester, MN 55905, USA.
¹¹ Departments of Oncology and Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.
¹² Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
¹³ Office of Cancer Clinical Proteomics Research, National Cancer Institute, Rockville, MD 20850, USA.
¹⁴ Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA.
¹⁵ Molecular Biology Core Facilities, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
¹⁶ Department of Pathology, Department of Computational Medicine and Bioinformatics, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
¹⁷ Institute for Systems Genetics, NYU School of Medicine, New York, NY 10016, USA.
¹⁸ Department of Molecular and Cellular Pharmacology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, and Institute for Data Science & Computing, University of Miami, Miami, FL 33136, USA.
¹⁹ Department of Public Health Sciences, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
²⁰ Helen Diller Family Comprehensive Cancer Center, Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA 94115, USA.
²¹ Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, Minneapolis, MN 55455, USA.
²² Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
²³ Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
²⁴ Department of Pathology, Department of Computational Medicine and Bioinformatics, Michigan Center for Translational Pathology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA. Electronic address: mcieslik@med.umich.edu.
²⁵ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: pei.wang@mssm.edu.
²⁶ Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. Electronic address: mjbirrer@uams.edu.
²⁷ Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. Electronic address: apaulovi@fredhutch.org.

Abstract

To improve the understanding of chemo-refractory high-grade serous ovarian cancers (HGSOCs), we characterized the proteogenomic landscape of 242 (refractory and sensitive) HGSOCs, representing one discovery and two validation cohorts across two biospecimen types (formalin-fixed paraffin-embedded and frozen). We identified a 64-protein signature that predicts with high specificity a subset of HGSOCs refractory to initial platinum-based therapy and is validated in two independent patient cohorts. We detected significant association between lack of Ch17 loss of heterozygosity (LOH) and chemo-refractoriness. Based on pathway protein expression, we identified 5 clusters of HGSOC, which validated across two independent patient cohorts and patient-derived xenograft (PDX) models. These clusters may represent different mechanisms of refractoriness and implicate putative therapeutic vulnerabilities.

Keywords: chemorefractory; high-grade serous ovarian cancer; machine learning; mass spectrometry; multiple reaction monitoring; platinum; precision oncology; predictive biomarker; prognostic biomarker; proteogenomic.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Cystadenocarcinoma, Serous* / drug therapy
Cystadenocarcinoma, Serous* / genetics
Female
Humans
Ovarian Neoplasms* / drug therapy
Ovarian Neoplasms* / genetics
Proteogenomics*

Abstract

Publication types

MeSH terms

Grants and funding