Detecting post-translational modification signatures as potential biomarkers in clinical mass spectrometry

<p><b>Introduction</b>: Numerous diseases are caused by changes in post-translational modifications (PTMs). Therefore, the number of clinical proteomics studies that include the analysis of PTMs is increasing. Combining complementary information—for example changes in protein abundance, PTM levels, with the genome and transcriptome (proteogenomics)—holds great promise for discovering important drivers and markers of disease, as variations in copy number, expression levels, or mutations <i>without</i> spatial/functional/isoform information is often insufficient or even misleading.</p> <p><b>Areas covered</b>: We discuss general considerations, requirements, pitfalls, and future perspectives in applying PTM-centric proteomics to clinical samples. This includes samples obtained from a human subject, for instance <i>(i)</i> bodily fluids such as plasma, urine, or cerebrospinal fluid, <i>(ii)</i> primary cells such as reproductive cells, blood cells, and <i>(iii)</i> tissue samples/biopsies.</p> <p><b>Expert commentary</b>: PTM-centric discovery proteomics can substantially contribute to the understanding of disease mechanisms by identifying signatures with potential diagnostic or even therapeutic relevance but may require coordinated efforts of interdisciplinary and eventually multi-national consortia, such as initiated in the cancer moonshot program. Additionally, robust and standardized mass spectrometry (MS) assays—particularly targeted MS, MALDI imaging, and immuno-MALDI—may be transferred to the clinic to improve patient stratification for precision medicine, and guide therapies.