Cancer is the second leading cause of death globally. One of the main hallmarks in cancer is the functional deregulation of crucial molecular pathways via driver genetic events that lead to abnormal gene expression, giving cells a selective growth advantage. Driver events are defined as mutations, fusions and copy number alterations that are causally implicated in oncogenesis. Molecular analysis on tissues that have originated from a wide range of anatomical areas has shown that mutations in different members of several pathways are implicated in different cancer types. In recent decades, significant efforts have been made to incorporate this knowledge into daily medical practice, providing substantial insight towards clinical diagnosis and personalized therapies. However, since there is still a strong need for more effective drug development, a deep understanding of the involved signaling mechanisms and the interconnections between these pathways is highly anticipated. Here, we perform a systemic analysis on cancer patients included in the Pan-Cancer Atlas project, with the aim to select the ten most highly mutated signaling pathways (p53, RTK-RAS, lipids metabolism, PI-3-Kinase/Akt, ubiquitination, b-catenin/Wnt, Notch, cell cycle, homology directed repair (HDR) and splicing) and to provide a detailed description of each pathway, along with the corresponding therapeutic applications currently being developed or applied. The ultimate scope is to review the current knowledge on highly mutated pathways and to address the attractive perspectives arising from ongoing experimental studies for the clinical implementation of personalized medicine.

Biomedical Applications Unit Institute of Chemical Biology National Hellenic Research Foundation 48 Vassileos Constantinou Avenue 11635 Athens Greece

Department of Medical Biosciences Umeå University 90185 Umeå Sweden

Inserm UMRS1131 Institut de Génétique Moléculaire Université Paris 7 Hôpital St Louis F 75010 Paris France

Institut de Biotecnologia i de Biomedicina Universitat Autònoma de Barcelona 08193 Barcelona Spain

International Centre for Cancer Vaccine Science University of Gdansk 80 822 Gdansk Poland

Research Centre for Applied Molecular Oncology Masaryk Memorial Cancer Institute 65653 Brno Czech Republic

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The Elephant Evolved p53 Isoforms that Escape MDM2-Mediated Repression and Cancer