Pan-cancer antagonistic inhibition pattern of ATM-driven G2/M checkpoint pathway vs other DNA repair pathways.

Autor: Zolotovskaia MA; Laboratory for Translational Genomic Bioinformatics, Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region 141701, Russia; Omicsway Corp., Walnut, CA, 91789, USA. Electronic address: zolotovskaia.ma@mipt.ru., Modestov AA; Laboratory for Translational Genomic Bioinformatics, Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region 141701, Russia; Laboratory for Clinical and Genomic Bioinformatics, I.M. Sechenov First Moscow State Medical University, Moscow 119991, Russia., Suntsova MV; Laboratory for Translational Genomic Bioinformatics, Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region 141701, Russia; World-Class Research Center 'Digital biodesign and personalized healthcare', Sechenov First Moscow State Medical University, Moscow, Russia., Rachkova AA; Laboratory for Translational Genomic Bioinformatics, Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region 141701, Russia; Laboratory for Clinical and Genomic Bioinformatics, I.M. Sechenov First Moscow State Medical University, Moscow 119991, Russia., Koroleva EV; Laboratory for Translational Genomic Bioinformatics, Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region 141701, Russia., Poddubskaya EV; Laboratory for Clinical and Genomic Bioinformatics, I.M. Sechenov First Moscow State Medical University, Moscow 119991, Russia., Sekacheva MI; Laboratory for Clinical and Genomic Bioinformatics, I.M. Sechenov First Moscow State Medical University, Moscow 119991, Russia., Tkachev VS; Oncobox Ltd., Moscow 121205, Russia., Garazha AV; Omicsway Corp., Walnut, CA, 91789, USA; Oncobox Ltd., Moscow 121205, Russia., Glusker AA; Laboratory for Clinical and Genomic Bioinformatics, I.M. Sechenov First Moscow State Medical University, Moscow 119991, Russia., Seryakov AP; Department of Oncology, Medical Holding SM-Clinic, 105120 Moscow, Russia., Vladimirova US; Laboratory for Clinical and Genomic Bioinformatics, I.M. Sechenov First Moscow State Medical University, Moscow 119991, Russia., Rumiantsev PO; Department of Nuclear Medicine, Endocrinology Research Centre, Moscow 117312, Russia., Moisseev AA; Laboratory for Clinical and Genomic Bioinformatics, I.M. Sechenov First Moscow State Medical University, Moscow 119991, Russia., Zharkov DO; Laboratory for Protein Engineering, Novosibirsk State University, Novosibirsk 630090, Russia; Laboratory for Genomic and Protein Engineering, SB RAS Institute of Chemical Biology and Fundamental Medicine, Novosibirsk 630090, Russia., Kuzmin DV; Laboratory for Translational Genomic Bioinformatics, Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region 141701, Russia., Zhao X; Core Laboratory, The Affiliated Qingdao Central Hospital of Qingdao University, Qingdao 266042 China., Prassolov VS; Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia., Shegay PV; National Medical Research Radiological Center of the Ministry of Health of the Russian Federation, 249036 Obninsk, Russia., Li X; UCLA Technology Center for Genomics & Bioinformatics, Department of Pathology & Laboratory Medicine, Los Angeles, CA 90095, USA., Steinbichler TB; Tyrolean Cancer Research Institute, Innsbruck, Austria., Kim E; Clinic for Neurosurgery, Laboratory of Experimental Neurooncology, Johannes Gutenberg University Medical Centre, Langenbeckstrasse 1, 55124 Mainz, Germany., Sorokin MI; Laboratory for Translational Genomic Bioinformatics, Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region 141701, Russia; Omicsway Corp., Walnut, CA, 91789, USA; Laboratory for Clinical and Genomic Bioinformatics, I.M. Sechenov First Moscow State Medical University, Moscow 119991, Russia; Laboratory for Genomic Analysis of Signaling Systems, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russia., Wang Y; Core Laboratory, The Affiliated Qingdao Central Hospital of Qingdao University, Qingdao 266042 China. Electronic address: yewang@qdu.edu.cn., Buzdin AA; Laboratory for Translational Genomic Bioinformatics, Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region 141701, Russia; World-Class Research Center 'Digital biodesign and personalized healthcare', Sechenov First Moscow State Medical University, Moscow, Russia; Laboratory for Genomic Analysis of Signaling Systems, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russia; PathoBiology Group, European Organization for Research and Treatment of Cancer (EORTC), Brussels, Belgium.
Jazyk: angličtina
Zdroj: DNA repair [DNA Repair (Amst)] 2023 Mar; Vol. 123, pp. 103448. Date of Electronic Publication: 2023 Jan 13.
DOI: 10.1016/j.dnarep.2023.103448
Abstrakt: DNA repair mechanisms keep genome integrity and limit tumor-associated alterations and heterogeneity, but on the other hand they promote tumor survival after radiation and genotoxic chemotherapies. We screened pathway activation levels of 38 DNA repair pathways in nine human cancer types (gliomas, breast, colorectal, lung, thyroid, cervical, kidney, gastric, and pancreatic cancers). We took RNAseq profiles of the experimental 51 normal and 408 tumor samples, and from The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium databases - of 500/407 normal and 5752/646 tumor samples, and also 573 normal and 984 tumor proteomic profiles from Proteomic Data Commons portal. For all the samplings we observed a congruent trend that all cancer types showed inhibition of G2/M arrest checkpoint pathway compared to the normal samples, and relatively low activities of p53-mediated pathways. In contrast, other DNA repair pathways were upregulated in most of the cancer types. The G2/M checkpoint pathway was statistically significantly downregulated compared to the other DNA repair pathways, and this inhibition was strongly impacted by antagonistic regulation of (i) promitotic genes CCNB and CDK1, and (ii) GADD45 genes promoting G2/M arrest. At the DNA level, we found that ATM, TP53, and CDKN1A genes accumulated loss of function mutations, and cyclin B complex genes - transforming mutations. These findings suggest importance of activation for most of DNA repair pathways in cancer progression, with remarkable exceptions of G2/M checkpoint and p53-related pathways which are downregulated and neutrally activated, respectively.
Competing Interests: Conflict of interest statement Authors Anton Buzdin and Andrew Garazha were employed by the company OmicsWay Corp., and Victor Tkachev, Andrew Garazha, and Maxim Sorokin were employed by the company Oncobox Ltd. The remaining authors have only academic or clinical affiliations. All the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2023 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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