title: Serum degradome markers for the detection of breast cancer.
abstract: Many proteins have been proposed as potential biomarkers for breast cancer. Yet, validation of their discriminative value using quantitative methods has scarcely been performed. In this study, we investigated the discriminative value of six peptides that were previously proposed to be generated by breast cancer specific exoproteases: bradykinin, des-Arg(9)-bradykinin, Hyp(3)-bradykinin, and fragments of fibrinogen alpha-chain (Fib-alpha ([605-629])), complement component 4a (C4a ([1337-1350])), and interalpha trypsin inhibitor heavy chain 4 (ITIH4 ([666-687])). Their absolute serum concentrations were measured with a completely validated liquid chromatography-tandem mass spectrometric assay (LC-MS/MS) and compared between 62 newly diagnosed breast cancer patients and 62 controls matched for age and sample storage duration. Both ITIH4 ([666-687]) and des-Arg(9)-bradykinin showed statistically significantly higher median concentrations in breast cancer samples than in matched control samples. Additionally, we analyzed serum samples collected after surgical removal of the tumor, in which median ITIH4 ([666-687]) and des-Arg(9)-bradykinin concentrations were significantly decreased and not statistically significantly different from concentrations in the controls anymore. In a combined analysis, ITIH4 (666-687]) and des-Arg(9)-bradykinin independently contributed to the discrimination between cases and controls. In this study, we confirmed that the exoprotease breakdown peptides, ITIH4 (666-687]) and des-Arg(9)-bradykinin, differed between breast cancer cases and controls, supporting the potential of degradome markers for the diagnosis of breast cancer.
authors.affiliation: Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, The Netherlands.
authors.forename: Annemieke W J
authors.initials: AW
authors.lastname: van Winden
authors.forename: Irene
authors.initials: I
authors.lastname: van den Broek
authors.forename: Marie-Christine W
authors.initials: MC
authors.lastname: Gast
authors.forename: Judith Y M N
authors.initials: JY
authors.lastname: Engwegen
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Sparidans
authors.forename: Eric J
authors.initials: EJ
authors.lastname: van Dulken
authors.forename: Annekatrien C T M
authors.initials: AC
authors.lastname: Depla
authors.forename: Annemieke
authors.initials: A
authors.lastname: Cats
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
authors.forename: Petra H M
authors.initials: PH
authors.lastname: Peeters
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: Carla H
authors.initials: CH
authors.lastname: van Gils
mesh_terms: D000368:Aged; D000595:Amino Acid Sequence; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000097:blood*; D001798:Blood Proteins / Q000235:genetics; D001920:Bradykinin / Q000097:blood / Q000235:genetics; D001943:Breast Neoplasms / Q000097:blood* / Q000175:diagnosis*; D016022:Case-Control Studies; D002853:Chromatography, Liquid; D015934:Complement C4a / Q000032:analysis / Q000235:genetics; D005260:Female; D005340:Fibrinogen / Q000032:analysis / Q000235:genetics; D006023:Glycoproteins / Q000097:blood / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D008969:Molecular Sequence Data; D009426:Netherlands; D053491:Proteinase Inhibitory Proteins, Secretory / Q000097:blood / Q000235:genetics; D040901:Proteomics / Q000379:methods; D053719:Tandem Mass Spectrometry
chemical_list: D014408:Biomarkers, Tumor; D001798:Blood Proteins; D006023:Glycoproteins; C091236:ITIH4 protein, human; D053491:Proteinase Inhibitory Proteins, Secretory; C464794:fibrinogen Aalpha; D015934:Complement C4a; D005340:Fibrinogen; D001920:Bradykinin