12 CHAPTER 1 that form a protein26. All proteins in an organism together are called the proteome. Through regulation of gene expression, cellular functions can be controlled. Another way that the function and activity of proteins are regulated is through reversible chemical changes to the protein after translation, known as posttranslational modifications (PTM). Phosphorylation is one of the most common PTM. During phosphorylation, a phosphate group is added to one of the amino acids tyrosine, serine or threonine by a kinase, thereby regulating the protein function. Especially tyrosine phosphorylation (pTyr) plays an important role in the regulation of signaling cascades in cancer. All phosphorylated proteins together are called the phosphoproteome. GENOMICS-BASED PRECISION ONCOLOGY The development of a large number of targeted- and immunotherapies, targeting specific molecular alterations and aberrant pathways in tumor cells, has dramatically changed the treatment paradigm in oncology. Coming from a histology-centered one-size-fits-all approach, the major focus has now shifted to precision oncology, a patient-centered biomarker-driven personalized approach to systemic treatment of patients with cancer21. Precision oncology is also known in literature as “personalized oncology”, “personalized cancer medicine” or “precision cancer medicine”. Many targeted- and immunotherapies have already received FDA/EMA approval and are available for patients with certain tumor types, harboring a specific molecular feature that predicts sensitivity for these drugs9,22-24. Though this is an important step towards precision oncology, the maximum potential of this approach is currently not used. A pan-cancer whole-genome analysis of metastatic solid tumors showed that in 31% of patients, across tumor types, an “actionable” genomic event was identified that predicted sensitivity to a drug. In 18% this was a biomarker for which on-label medication was available, and 13% of patients had a genomic target for which drugs were available, but not for the tumor type25. Due to the histology-specific registrations of these drugs, a significant number of patients with other tumor types harboring the qualifying genomic aberration does not have access to these potentially active treatment options. Clinical evidence for efficacy of these drugs in other tumor types is often not available, and large trials with conventional design are usually not feasible due to the small and diverse subgroups of patients. PROTEOME- AND MULTI-OMICS-BASED PRECISION ONCOLOGY For the identification of tissue-based biomarkers, research often focused on abnormal protein expression, as found by immunohistochemistry, or genomic aberrations, such as activating mutations or amplifications of oncogenes or deletions of tumor suppressor genes, as found by targeted or broad panel sequencing. With recent advancements in sequencing- and bioinformatics techniques, also more complex genomic features such as gene fusions, microsatellite instability (MSI) and homologous repair deficiency (HRD) signatures can be computed and may serve as genomic biomarkers for treatment response to targeted agents.
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