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

• DOI: 10.1016/j.cell.2023.07.004
• Publication Date: 2023-08-03T14:42:26Z
• Authors: 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 L...; 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. Nesvizh...; Bing Zhang; Jeffrey R. Whiteaker; David Fenyo; Wilson McKerrow; Joshua Wang; Stephan C. Schürer; Vasileios Stathias; X. Steven Chen; Mary Helen Barcel...; 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
• Keywords: multiple reaction monitoring; Medical Sciences; Bioinformatics; Cystadenocarcinoma; 610; Article; Biomedical Informatics; proteogenomic; high-grade serous ovarian cancer; 616; Medical Specialties; Medicine and Health Sciences; Humans; platinum; predictive biomarker; prognostic biomarker; mass spectrometry; Proteogenomics; Ovarian Neoplasms; Serous; 3. Good health; Cystadenocarcinoma, Serous; machine learning; Oncology; precision oncology; chemorefractory; Female

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.