title: Cancer genetics-guided discovery of serum biomarker signatures for diagnosis and prognosis of prostate cancer.
abstract: 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.
authors.affiliation: Institute of Cell Biology, Eidgenössische Technische Hochschule Zurich, 8093 Zurich, Switzerland.
authors.forename: Igor
authors.initials: I
authors.lastname: Cima
authors.forename: Ralph
authors.initials: R
authors.lastname: Schiess
authors.forename: Peter
authors.initials: P
authors.lastname: Wild
authors.forename: Martin
authors.initials: M
authors.lastname: Kaelin
authors.forename: Peter
authors.initials: P
authors.lastname: Schüffler
authors.forename: Vinzenz
authors.initials: V
authors.lastname: Lange
authors.forename: Paola
authors.initials: P
authors.lastname: Picotti
authors.forename: Reto
authors.initials: R
authors.lastname: Ossola
authors.forename: Arnoud
authors.initials: A
authors.lastname: Templeton
authors.forename: Olga
authors.initials: O
authors.lastname: Schubert
authors.forename: Thomas
authors.initials: T
authors.lastname: Fuchs
authors.forename: Thomas
authors.initials: T
authors.lastname: Leippold
authors.forename: Stephen
authors.initials: S
authors.lastname: Wyler
authors.forename: Jens
authors.initials: J
authors.lastname: Zehetner
authors.forename: Wolfram
authors.initials: W
authors.lastname: Jochum
authors.forename: Joachim
authors.initials: J
authors.lastname: Buhmann
authors.forename: Thomas
authors.initials: T
authors.lastname: Cerny
authors.forename: Holger
authors.initials: H
authors.lastname: Moch
authors.forename: Silke
authors.initials: S
authors.lastname: Gillessen
authors.forename: Ruedi
authors.initials: R
authors.lastname: Aebersold
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Krek
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000097:blood*; D019295:Computational Biology; D020868:Gene Silencing; D006023:Glycoproteins / Q000097:blood; D006801:Humans; D008297:Male; D008722:Methods; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000032:analysis / Q000235:genetics; D011471:Prostatic Neoplasms / Q000175:diagnosis*; D040901:Proteomics / Q000379:methods*
chemical_list: D014408:Biomarkers, Tumor; D006023:Glycoproteins; D051059:PTEN Phosphohydrolase