Urinary proteomics signature of malignancy post heart transplantation is associated with mortality risk

Abstract

Abstract Background Heart transplant recipients are at an increased risk of malignancy that has an adverse impact on outcomes. The surveillance of malignancy after heart transplantation is cumbersome and involves multidisciplinary efforts. Purpose This study aimed to identify potential urinary proteomic biomarkers for the detection of malignancy and their predictive value for mortality risk after heart transplantation. Methods Urinary samples from 343 heart transplant recipients, including 27 with solid organ cancer, 23 with skin cancer, and 293 without cancer, were measured at baseline by capillary electrophoresis coupled with mass spectrometry. Multivariable logistic regression models and partial least squares-discriminant analysis were used to identify proteome differences between cancer and non-cancer patients. The association between proteomic signatures and mortality was assessed by Cox regression analysis. Results The urinary proteomics difference between solid organ cancer and non-cancer was 30 peptides involved in collagen degradation, cell adhesion and apoptosis, and tumorigenesis. The proteomic signature of skin cancer was comprised of 39 peptides related to collagen turnover, cell migration and invasion, and proliferation. These two proteomic signatures yielded an AUC of 0.93 (95% CI: 0.90-0.97) and 0.92 (0.88-0.97) for the detection of solid organ or skin cancer (P<0.0001), respectively. The corresponding AUCs provided by multiple clinical factors (sex, age, year after transplantation, immunosuppressive agents, blood pressure, HDL cholesterol, and eGFR) were 0.88 (0.82-0.93) and 0.82 (0.72-0.92). The proteomic signature of solid organ cancer (adjusted hazard ratio: 1.04 [1.01-1.07], P=0.007) and its constituted peptides (collagen type III and I, MLL cleavage product C180, and CD99 antigen-like protein 2) were significantly associated with mortality. Conclusions Urinary proteomic biomarkers might be used to screen malignancy after heart transplantation. Proteins involved in collagen metabolism, cell adhesion and proliferation, and tumorigenesis predicted cancer mortality after heart transplantation.Figure 1.WorkflowFigure 2.ROC curves