A key barrier to the realization of personalized medicine for cancer is the identification of biomarkers. Here we describe a two-stage strategy for the discovery of serum biomarker signatures corresponding to specific cancer-causing mutations and its application to prostate cancer (PCa) in the context of the commonly occurring phosphatase and tensin homolog (PTEN) tumor-suppressor gene inactivation. In the first stage of our approach, we identified 775 N-linked glycoproteins from sera and prostate tissue of wild-type and Pten-null mice. Using label-free quantitative proteomics, we showed that Pten inactivation leads to measurable perturbations in the murine prostate and serum glycoproteome. Following bioinformatic prioritization, in a second stage we applied targeted proteomics to detect and quantify 39 human ortholog candidate biomarkers in the sera of PCa patients and control individuals. The resulting proteomic profiles were analyzed by machine learning to build predictive regression models for tissue PTEN status and diagnosis and grading of PCa. Our approach suggests a general path to rational cancer biomarker discovery and initial validation guided by cancer genetics and based on the integration of experimental mouse models, proteomics-based technologies, and computational modeling.serum biomarkers | mass spectrometry | Pten conditional knockout mouse model

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C.G. and M.S. contributed equallyquestionnaire with a mean follow-up of 22 months. RESULTSOperative duration was significantly longer in the RRN group compared with the ORN and NSS groups, at a mean (sem) of 146 (42) min vs 113 (48) min and 114 (42) min ( P < 0.001). In the RRN group intraoperative blood loss was lower than in the ORN and NSS groups, at a mean (sem) of 231 (153) mL vs 424 (361) mL and 494 (360) mL ( P < 0.001). Morbidity rates were 13.9% for RRN, 16.2% for ORN and 20.5% for NSS, the most relevant complications being bleeding requiring transfusions in RRN and NSS patients and haemorrhage (5% of patients in each group). Creatinine values at 6 months after surgery only recovered completely in the NSS group. Patients in the ORN group had a trend towards higher mental wellbeing scores than patients in the RRN and NSS groups, with a mean Mental Component Summary Score of 48.3 vs 48.0 and 44.5, respectively (not statistically significant), while all patients were in similar physical condition after surgery, with a mean Physical Component Summary Scores of 48.0 (ORN), 47.4 (RRN) and 47.2 (NSS). The physical condition scores of patients in all groups were higher than scores reached by an age and sex-matched population (45.8). CONCLUSIONThese real-world data show that each of the surgical techniques can be considered safe. Importantly, after surgery patients reported high QoL scores independent of the technique used.