813405420a9ac4376d9765217ad0af3a pmc_35158934.pdf a87c3e1abcf4eca8c5ea3c9b7f5fc0c966296850 pmc_35158934.pdf b3ed11088c7a5cee37164f26422ccda0471e105b253056dab9f1c544604bddc2 pmc_35158934.pdf Title: Targeting Oncogenic Pathways in the Era of Personalized Oncology: A Systemic Analysis Reveals Highly Mutated Signaling Pathways in Cancer Patients and Potential Therapeutic Targets Subject: 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. Keywords: molecular oncology; precision medicine; tumor; NGS; clinical implementation; cancer patients; mutations Author: Alexandros Karagiannakos, Maria Adamaki, Antonis Tsintarakis, Borek Vojtesek, Robin Fåhraeus, Vassilis Zoumpourlis and Konstantinos Karakostis Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Fri Jan 28 11:37:45 2022 CET ModDate: Sat Jan 29 04:57:22 2022 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 32 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 3128002 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- UTLBKU+VnURWPalladioL Type 1 Custom yes yes no 10 0 QIEZZP+URWPalladioL-Bold Type 1 Custom yes yes no 15 0 DEHUYV+URWPalladioL-Roma Type 1 Custom yes yes no 20 0 OKLKJD+URWPalladioL-Ital Type 1 Custom yes yes no 24 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 32 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 36 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 40 0 LCJEVJ+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 53 0 ABCDEE+Palatino Linotype,Bold TrueType WinAnsi yes yes no 86 0 ABCDEE+Palatino Linotype TrueType WinAnsi yes yes no 90 0 ABCDEE+Palatino Linotype,Italic TrueType WinAnsi yes yes no 94 0 Times New Roman TrueType WinAnsi no no no 98 0 ABCDEE+Palatino Linotype,Bold TrueType WinAnsi yes yes no 110 0 ABCDEE+Palatino Linotype TrueType WinAnsi yes yes no 114 0 ABCDEE+Palatino Linotype,Italic TrueType WinAnsi yes yes no 118 0 ABCDEE+Palatino Linotype,Bold TrueType WinAnsi yes yes no 131 0 ABCDEE+Palatino Linotype TrueType WinAnsi yes yes no 135 0 ABCDEE+Palatino Linotype,Italic TrueType WinAnsi yes yes no 139 0 ABCDEE+Palatino Linotype,Bold TrueType WinAnsi yes yes no 151 0 ABCDEE+Palatino Linotype TrueType WinAnsi yes yes no 155 0 ABCDEE+Palatino Linotype,Italic TrueType WinAnsi yes yes no 159 0 ABCDEE+Palatino Linotype CID TrueType Identity-H yes yes yes 163 0 SOSCBV+CMSY10 Type 1 Builtin yes yes no 175 0 ABCDEE+Palatino Linotype,Bold TrueType WinAnsi yes yes no 183 0 ABCDEE+Palatino Linotype TrueType WinAnsi yes yes no 187 0 ABCDEE+Palatino Linotype,Italic TrueType WinAnsi yes yes no 191 0 ABCDEE+Palatino Linotype CID TrueType Identity-H yes yes yes 195 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2022-07-01 02:26:35 CEST RepresentationInformation: pmc_35158934.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2022-02-27 18:44:35 CET Size: 3128002 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 977 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Personalized Therapeutic Strategies Require Understanding of the Underlying Signaling Pathways’ Mechanisms Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4923ab24 Item: Title: Systemic Analysis Determines Prevalent Mutated Carcinogenic Pathways Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@44c8afef Item: Title: The p53 Pathway Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Item: Title: The RTK-RAS Pathway Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: Lipid Metabolism Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: The PI3K/AKT Pathway Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: Ubiquitination and Acetylation Pathways Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: The WNT/b Catenin Pathway Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: The Notch Pathway Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: The Cell Cycle Pathway Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: The HDR Pathway Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: The Splicing Pathway Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: Conclusive Remarks Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Info: Title: Targeting Oncogenic Pathways in the Era of Personalized Oncology: A Systemic Analysis Reveals Highly Mutated Signaling Pathways in Cancer Patients and Potential Therapeutic Targets Author: Alexandros Karagiannakos, Maria Adamaki, Antonis Tsintarakis, Borek Vojtesek, Robin Fåhraeus, Vassilis Zoumpourlis and Konstantinos Karakostis Subject: 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. 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