title: The intricacy of biomarker complexity-the identification of a genuine proteomic biomarker is more complicated than believed.
abstract: Several reasons have been put forward to explain the irreproducibility of proteomic biomarker search. However, these reasons pertain to almost every part of biomarker search across the entire analytical workflow but are entirely experimental or methodological. However, in this article we point out that there is a further cause of such irreproducibility. This is not an additional methodological or experimental cause but arises directly from the biology of protein expression. It arises from the fact that disease changes the diversity within protein families. This cause of irreproducibility has been very little studied in relation to proteomic biomarker search. Gene expression is highly variable even in healthy people. Therefore, multiple proteoforms are also to be expected when gene expression is disrupted by disease, proteoforms that may be differently altered by pathology. In consequence, it is illogical to expect that the whole protein family produces a reliably usable biomarker. It is more reasonable to expect that a specific proteoform fulfills this role. Appropriate sample pre-fractionation methods and data analyses could help to identify this version, carrying the modification or the epitope required.
authors.affiliation: Institute of Biochemistry I, University Hospital Jena, Jena, Germany.
authors.forename: Rita
authors.initials: R
authors.lastname: Büchler
authors.affiliation: Institute of Biochemistry I, University Hospital Jena, Jena, Germany.
authors.forename: Sindy
authors.initials: S
authors.lastname: Wendler
authors.affiliation: Institute of Biochemistry I, University Hospital Jena, Jena, Germany.|Clinic of Neurology, University Hospital Jena, Jena, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Muckova
authors.affiliation: Clinic of Neurology, University Hospital Jena, Jena, Germany.
authors.forename: Julian
authors.initials: J
authors.lastname: Großkreutz
authors.affiliation: Institute of Biochemistry I, University Hospital Jena, Jena, Germany.
authors.forename: Heidrun
authors.initials: H
authors.lastname: Rhode
mesh_terms: D015415:Biomarkers / Q000032:analysis*; D015180:Electrophoresis, Gel, Two-Dimensional; D004797:Enzyme-Linked Immunosorbent Assay; D011506:Proteins / Q000032:analysis; D040901:Proteomics
chemical_list: D015415:Biomarkers; D011506:Proteins
keywords: Biomarker heterogeneity; Protein species; Proteoforms