TY - JOUR

T1 - Pan-cancer antagonistic inhibition pattern of ATM-driven G2/M checkpoint pathway vs other DNA repair pathways

AU - Zolotovskaia, Marianna A

AU - Modestov, Alexander A

AU - Suntsova, Maria V

AU - Rachkova, Anastasia A

AU - Koroleva, Elena V

AU - Poddubskaya, Elena V

AU - Sekacheva, Marina I

AU - Tkachev, Victor S

AU - Garazha, Andrew V

AU - Glusker, Alexander A

AU - Seryakov, Aleksander P

AU - Vladimirova, Uliana S

AU - Rumiantsev, Pavel O

AU - Moisseev, Aleksey A

AU - Zharkov, Dmitry O

AU - Kuzmin, Denis V

AU - Zhao, Xiaowen

AU - Prassolov, Vladimir S

AU - Shegay, Petr V

AU - Li, Xinmin

AU - Steinbichler, Teresa B

AU - Kim, Ella

AU - Sorokin, Maxim I

AU - Wang, Ye

AU - Buzdin, Anton A

N1 - Acknowledgements: We thank Oncobox NCT03724097 clinical trial team for the cooperation and providing biomaterials and databases. This study was made possible through the technical support of the Applied Genetics Resource Facility of MIPT, support 075–15-2021–684. We cordially thank Dr. Julian. M. Rozenberg for suggestions. Copyright © 2023 Elsevier B.V. All rights reserved.

PY - 2023/3

Y1 - 2023/3

N2 - 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.

AB - 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.

KW - G2/M arrest pathway

KW - Molecular pathway analysis

KW - Oncobox clinical investigation

KW - Proteomic profiling

KW - RNA sequencing

KW - Systems biology

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85146460500&origin=inward&txGid=faa08ad214278f831fa339808be2defa

UR - https://www.mendeley.com/catalogue/86629477-5e9b-3c0f-ae17-f841c2456f21/

U2 - 10.1016/j.dnarep.2023.103448

DO - 10.1016/j.dnarep.2023.103448

M3 - Article

C2 - 36657260

VL - 123

JO - DNA Repair

JF - DNA Repair

SN - 1568-7864

M1 - 103448

ER -