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

Zolotovskaia, Marianna; Modestov, Alexander A.; Suntsova, Maria; Rachkova, Anastasia A.; Koroleva, Elena V.; Poddubskaya, Elena; Sekacheva, Marina; Tkachev, Victor; Garazha, Andrew; Glusker, Alexander; Seryakov, Aleksander; Vladimirova, Uliana; Румянцев, П. О.; Moisseev, Aleksey; Жарков, Д. О.; Kuzmin, Denis; Zhao, Xiaowen; Prassolov, Vladimir; Shegay, Peter; Li, Xinmin; Steinbichler, Teresa Bernadette; Kim, Ella; Sorokin, Maxim; Wang, Ye; Buzdin, Anton

doi:10.1016/j.dnarep.2023.103448

Cited by 10 publications

(5 citation statements)

References 58 publications

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“…Note that the majority (32/38, 84%) of DNA repair pathways was statistically significantly upregulated in TERT + compared to TERT - cancers ( Supplementary Figure S2 ), except for the three pathways related to ATM mediated control of G2M cell cycle checkpoint and survival and three other pathways related to p53 control of DNA integrity and survival ( Supplementary Figure S2 ). This trend fits previous figure of incremental increase in activation of the same 32/38 pathways in the range: healthy human normal tissue — tumor adjacent pathologically normal tissue — benign tumor — malignant tumor, with the opposite regulation for the six pathways related to ATM and p53 replication control ( Vladimirova et al, 2021 ; Sorokin et al, 2023 ; Zolotovskaia et al, 2023 ).…”

Section: Resultssupporting

confidence: 89%

“…Pathway activation level (PAL) is an integral quantitative and qualitative characteristic of changes in the expression levels for genes participating in a molecular pathway ( Aliper et al, 2017 ; Buzdin et al, 2018 ; Borisov et al, 2020 ; Zolotovskaia et al, 2023 ).…”

Section: Methodsmentioning

confidence: 99%

“…PAL values were calculated as follows:

where PAL p is PAL for a pathway p , CNR n is the case-to-normal ratio for a gene n ; ARR (activator/repressor role) is a Boolean value that depends on the function of this gene product in the pathway p ( Zolotovskaia et al, 2023 ). ARR np is a Boolean value defined as follows: −1 when the product of the gene n inhibits the pathway p ; 1 when the product of n activates p ; 0 when the product of n has an ambiguous role in p .…”

Section: Methodsmentioning

confidence: 99%

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Pan-cancer experimental characteristic of human transcriptional patterns connected with telomerase reverse transcriptase (TERT) gene expression status

Drobyshev,

Modestov,

Suntsova

et al. 2024

Front. Genet.

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The TERT gene encodes the reverse transcriptase subunit of telomerase and is normally transcriptionally suppressed in differentiated human cells but reactivated in cancers where its expression is frequently associated with poor survival prognosis. Here we experimentally assessed the RNA sequencing expression patterns associated with TERT transcription in 1039 human cancer samples of 27 tumor types. We observed a bimodal distribution of TERT expression where ∼27% of cancer samples did not express TERT and the rest showed a bell-shaped distribution. Expression of TERT strongly correlated with 1443 human genes including 103 encoding transcriptional factor proteins. Comparison of TERT- positive and negative cancers showed the differential activation of 496 genes and 1975 molecular pathways. Therein, 32/38 (84%) of DNA repair pathways were hyperactivated in TERT+ cancers which was also connected with accelerated replication, transcription, translation, and cell cycle progression. In contrast, the level of 40 positive cell cycle regulator proteins and a set of epithelial-to-mesenchymal transition pathways was specific for the TERT- group suggesting different proliferation strategies for both groups of cancer. Our pilot study showed that the TERT+ group had ∼13% of cancers with C228T or C250T mutated TERT promoter. However, the presence of promoter mutations was not associated with greater TERT expression compared with other TERT+ cancers, suggesting parallel mechanisms of its transcriptional activation in cancers. In addition, we detected a decreased expression of L1 retrotransposons in the TERT+ group, and further decreased L1 expression in promoter mutated TERT+ cancers. TERT expression was correlated with 17 genes encoding molecular targets of cancer therapeutics and may relate to differential survival patterns of TERT- positive and negative cancers.

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Section: Resultssupporting

confidence: 89%

Section: Methodsmentioning

confidence: 99%

“…PAL values were calculated as follows:

Section: Methodsmentioning

confidence: 99%

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Pan-cancer experimental characteristic of human transcriptional patterns connected with telomerase reverse transcriptase (TERT) gene expression status

Drobyshev,

Modestov,

Suntsova

et al. 2024

Front. Genet.

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“…They can influence activities of intrinsic signaling pathways of the neighboring cells to better detach and invade in the form of circulating tumor cells [15] . The specific DNA repair pathway activation profiles there were strongly connected between the tumor and the corresponding matched normal tissues, which directly indicates their molecular interplay [9] , [16] . Thus, tumor matched “normal” tissues can be pathologically biased.…”

Section: Introductionmentioning

confidence: 82%

Large-scale assessment of pros and cons of autopsy-derived or tumor-matched tissues as the norms for gene expression analysis in cancers

Sorokin,

Buzdin,

Guryanova

et al. 2023

Computational and Structural Biotechnology Journal

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“…For example, E2F target and G2M checkpoint genes were significantly up-regulated in the high SGS group. This suggests that the cancer cells of BC patients in the high SGS group may have a higher proliferation capacity and higher malignant potential [ 24 , 25 ]. Some pathways, such as mTOR and MYC pathways, were also found to be significantly upregulated in the high SGS group.…”

Section: Discussionmentioning

confidence: 99%

Construction of stemness gene score by bulk and single-cell transcriptome to characterize the prognosis of breast cancer

Lin,

Feng,

Liu

et al. 2023

Aging

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Breast cancer (BC) is a heterogeneous disease characterized by significant differences in prognosis and therapy response. Numerous prognostic tools have been developed for breast cancer. Usually these tools are based on bulk RNA-sequencing (RNA-Seq) and ignore tumor heterogeneity. Consequently, the goal of this study was to construct a single-cell level tool for predicting the prognosis of BC patients. In this study, we constructed a stemness-risk gene score (SGS) model based on single-sample gene set enrichment analysis (ssGSEA). Patients were divided into two groups based on the median SGS. Patients with a high SGS scores had a significantly worse prognosis than those with a low SGS, and these groups exhibited differences in several tumor characteristics, such as immune infiltration, gene mutations, and copy number variants. Our results indicate that the SGS is a reliable tool for predicting prognosis and response to immunotherapy in BC patients.

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

Cited by 10 publications

References 58 publications

Pan-cancer experimental characteristic of human transcriptional patterns connected with telomerase reverse transcriptase (TERT) gene expression status

Pan-cancer experimental characteristic of human transcriptional patterns connected with telomerase reverse transcriptase (TERT) gene expression status

Large-scale assessment of pros and cons of autopsy-derived or tumor-matched tissues as the norms for gene expression analysis in cancers

Construction of stemness gene score by bulk and single-cell transcriptome to characterize the prognosis of breast cancer

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