Journal Article Ahead of print
PubMed: 42581747 DOI: 10.1002/ijc.70687
Sex-Specific Proteomic Profiling Identifies Pregnancy Zone Protein as a Complement-Linked Marker of Adverse Prognosis in Esophageal Adenocarcinoma.
Int J Cancer
Authors: Alexander Quaas, Hanna Schiemann, Su Ir Lyu, Thomas Zander, Axel Hillmer, Hans Schlößer, Christiane J Bruns, Reinhard Büttner, Bastian Grothey
Affiliations
- Institute of Pathology, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany.
- Department of Internal Medicine I, University Hospital Cologne, Medical Faculty, University of Cologne, Cologne, Germany.
- Department of General, Visceral and Cancer Surgery, Faculty of Medicine, University Hospital of Cologne, Cologne, Germany.
Abstract
Esophageal adenocarcinoma (EAC) exhibits marked male predominance with male-to-female ratios reaching 8.5:1, yet the molecular basis underlying this sex disparity remains poorly characterized. We analyzed 92 EAC specimens using mass spectrometry-based proteomics, comprising 47 female and 45 male tumors from treatment-naïve patients. Differential expression, pathway enrichment, immunohistochemical, and survival analyses were used to identify sex-associated proteomic features and prognostic signatures. Proteomic profiling revealed focal yet biologically meaningful sex differences in EAC. After multiple testing correction, three proteins were differentially expressed: the autosomal protein pregnancy zone protein (PZP), enriched in female tumors, and the Y-chromosome-encoded proteins DDX3Y and RPS4Y1, which were overexpressed in male tumors. At nominal significance, proteins upregulated in female tumors showed marked enrichment of immune-related pathways. Proteins correlated with PZP expression formed a network dominated by complement cascade. Clinically, elevated PZP expression was associated with significantly poorer overall survival specifically in male patients, with no significant association detected in the combined or female-only cohort. Proteome-wide survival analyses further demonstrated distinct sex-specific prognostic landscapes. Our study provides the first comprehensive characterization of sex-associated proteomic differences in EAC. Sex shapes immune-related pathways, prognostic proteomic signatures, and survival associations. PZP emerges as a sex-differential, complement-associated protein with adverse prognostic significance in male patients, highlighting sex as a biologically and clinically relevant variable in EAC.
MeSH
Pregnancy, Neoplasms, Adenocarcinoma, Survival Analysis, Proteomics, Sex Characteristics, Sex, Complement System Proteins, Prognosis, Sex Differences