A novel pan-cancer biomarker plasma heat shock protein 90alpha and its diagnosis determinants in clinic.

A sensitive and specific diagnosis biomarker, in principle scalable to most cancer types, is needed to reduce the prevalent cancer mortality. Meanwhile, the investigation of diagnosis determinants of a biomarker will facilitate the interpretation of its screening results in clinic. Here we design a large-scale (1558 enrollments), multicenter (multiple hospitals), and cross-validation (two datasets) clinic study to validate plasma Hsp90 alpha quantified by ELISA as a pan-cancer biomarker. ROC curve shows the optimum diagnostic cutoff is 69.19 ng/mL in discriminating various cancer patients from all controls (AUC 0.895, sensitivity 81.33% and specificity 81.65% in test cohort; AUC 0.893, sensitivity 81.72% and specificity 81.03% in validation cohort). Similar results are noted in detecting early-stage cancer patients. Plasma Hsp90 alpha maintains also broad-spectrum for cancer subtypes, especially with 91.78% sensitivity and 91.96% specificity in patients with AFP-limited liver cancer. In addition, we demonstrate levels of plasma Hsp90 alpha are determined by ADAM10 expression, which will affect Hsp90 alpha content in exosomes. Furthermore, Western blotting and PRM-based quantitative proteomics identify that partial false ELISA-negative patients secret high levels of plasma Hsp90 alpha. Mechanism analysis reveal that TGF beta-PKC gamma gene signature defines a distinct pool of hyperphosphorylated Hsp90 alpha at Theronine residue. In clinic, a mechanistically relevant population of false ELISA-negative patients express also higher levels of PKC gamma. In sum, plasma Hsp90 alpha is a novel pan-cancer diagnosis biomarker, and cancer diagnosis with plasma Hsp90 alpha is particularly effective in those patients with high expression of ADAM10, but may be insufficient to detect the patients with low ADAM10 and those with hyperphosphorylated Hsp90 alpha.