The role of DNA damage and repair in liver cancer

Gillman, Rhys; Floro, Kylie Lopes; Wankell, Miriam; Hebbard, Lionel

doi:10.1016/j.bbcan.2020.188493

Cited by 33 publications

(28 citation statements)

References 113 publications

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“…These lncRNAs were characterized as genomic instability-related lncRNAs. Functional enrichment analysis of mRNAs co-expressed with 245 lncRNAs indicated that these lncRNAs may play an important role in the pathogenesis, DNA damage, and apoptosis pathways of HCC, which is consistent with other studies (Gillman et al, 2021). Abnormal repair of DNA damage is directly related to genomic stability (Tubbs and Nussenzweig, 2017).…”

Section: Discussionsupporting

confidence: 87%

Development and Validation of Genome Instability-Associated lncRNAs to Predict Prognosis and Immunotherapy of Patients With Hepatocellular Carcinoma

et al. 2022

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The pathophysiology of hepatocellular carcinoma (HCC) is prevalently related to genomic instability. However, research on the association of extensive genome instability lncRNA (GILnc) with the prognosis and immunotherapy of HCC remains scarce. We placed the top 25% of somatic mutations into the genetically unstable group and placed the bottom 25% of somatic mutations into the genetically stable group, and then to identify different expression of GILnc between the two groups. Then, LASSO was used to identify the most powerful prognostic GILnc, and a risk score for each patient was calculated according to the formula. Based on a computational frame, 245 different GILncs in HCC were identified. An eight GILnc model was successfully established to predict overall survival in HCC patients based on LASSO, then we divided HCC patients into high-risk and low-risk groups, and a significantly shorter overall survival in the high-risk group was observed compared to those in the low-risk group, and this was validated in GSE76427 and Tongji cohorts. GSEA revealed that the high-risk group was more likely to be enriched in cancer-specific pathways. Besides, the GILnc signature has greater prognostic significance than TP53 mutation status alone, and it is capable of identifying intermediate subtype groups existing with partial TP53 functionality in TP53 wild-type patients. Importantly, the high-risk group was associated with the therapeutic efficacy of PD-L1 blockade, suggesting that the development of potential drugs targeting these GILnc could aid the clinical benefits of immunotherapy. Finally, the GILnc signature model is better than the prediction performance of two recently published lncRNA signatures. In summary, we applied bioinformatics approaches to suggest that an eight GILnc model could serve as prognostic biomarkers to provide a novel direction to explore the pathogenesis of HCC.

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Section: Discussionsupporting

confidence: 87%

Development and Validation of Genome Instability-Associated lncRNAs to Predict Prognosis and Immunotherapy of Patients With Hepatocellular Carcinoma

et al. 2022

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“…However, the liver may not completely fall in this category, as hepatocytes keep their ability to replicate. Moreover, the liver, because of its biological functions such as detoxification, is exposed to multiple DNA damage agents, which may require it to be especially proficient for DNA repair [ 83 ]. Nonetheless, studying cccDNA formation in transformed cells can have its own biases and limitations.…”

Section: Conversion Of Rcdna To Cccdnamentioning

confidence: 99%

Early Steps of Hepatitis B Life Cycle: From Capsid Nuclear Import to cccDNA Formation

Dias

Sarica

Neuveut

2021

Viruses

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Hepatitis B virus (HBV) remains a major public health concern, with more than 250 million chronically infected people who are at high risk of developing liver diseases, including cirrhosis and hepatocellular carcinoma. Although antiviral treatments efficiently control virus replication and improve liver function, they cannot cure HBV infection. Viral persistence is due to the maintenance of the viral circular episomal DNA, called covalently closed circular DNA (cccDNA), in the nuclei of infected cells. cccDNA not only resists antiviral therapies, but also escapes innate antiviral surveillance. This viral DNA intermediate plays a central role in HBV replication, as cccDNA is the template for the transcription of all viral RNAs, including pregenomic RNA (pgRNA), which in turn feeds the formation of cccDNA through a step of reverse transcription. The establishment and/or expression of cccDNA is thus a prime target for the eradication of HBV. In this review, we provide an update on the current knowledge on the initial steps of HBV infection, from the nuclear import of the nucleocapsid to the formation of the cccDNA.

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“…It is closely related to hepatitis virus infection, aflatoxin, and bile acid to varying degrees ( Fattovich et al, 2004 ), these factors could cause DNA damage in hepatocytes and then trigger a series of cellular reactions, mainly including damage signal transduction and apoptosis induced by DNA repair ( Tanaka et al, 2008 ). If DNA damage could not be repaired correctly and accumulated continuously, it could lead to malignant transformation of hepatocytes and eventually lead to HCC ( Gillman et al, 2021 ). Therefore, DNA damage and repair (DDR) is an important molecular mechanism for the occurrence and development of HCC, and further study of it will lay a foundation for the comprehensive treatment of HCC.…”

Section: Discussionmentioning

confidence: 99%

A Five-Gene Signature Associated With DNA Damage Repair Molecular Subtype Predict Overall Survival for Hepatocellular Carcinoma

Huo

Fan

et al. 2022

Front. Genet.

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Background: DNA damage repair (DDR) is an important mechanism for the occurrence and development of hepatocellular carcinoma (HCC), but its impact on prognosis has not been fully understood.Materials and methods: A total of 904 HCC patients were included in our study, TCGA (n = 370) and GSE14520 (n = 239) were merged into a large-sample training cohort (n = 609). The training cohort was clustered into C1 and C2 based on prognostic DDR-related genes, the differentially expressed genes (DEGs) between C1 and C2 were identified by the Wilcoxon signed-rank test referred to criteria (|log2FC|≥1 and FDR< 0.05). The univariate Cox analysis was used to screen the prognostic-related DEGs, and Lasso penalized Cox regression analysis was used to construct the risk score. The patients were clarified into high- and low-risk groups based on the median risk score. ICGC (n = 231) and GSE116174 (n = 64) cohorts were used for external validation of the risk score’s prognostic value.Results: The Kaplan–Meier survival analysis showed that the high-risk group had a significantly reduced overall survival (OS) compared to the low-risk group in the three independent cohorts, and the time-dependent ROC curve showed that the five-gene (STMN1, PON1, PLOD2, MARCKSL1, and SPP1) risk score with a high accuracy in predicting OS. The patients with AFP >300 ng/ml, tumor poor differentiation (grade 3–4), micro and macro vascular tumor invasion, advanced stage (AJCC III-IV, BCLC stage B-C, and CLIP score >2) exhibited a higher risk score. Subgroup survival analysis found that the risk score was applicable to patients with different clinical characteristics. GO and KEGG functional enrichment analysis revealed that cell cycle, p53 signaling, TNF signaling-related pathways were upregulated in the high-risk group. The higher infiltration level of activated CD4 T cell, CD56 bright natural killer cell, plasmacytoid dendritic cell, and type 2 T helper cells were found to lead an unfavorable impact on the OS of HCC patients, and these four kinds of immune cells exhibited a higher infiltration level in the high-risk group.Conclusion: The five-gene risk score proposed in the research may provide new insights into the individualized evaluation of HCC prognosis.

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The role of DNA damage and repair in liver cancer

Cited by 33 publications

References 113 publications

Development and Validation of Genome Instability-Associated lncRNAs to Predict Prognosis and Immunotherapy of Patients With Hepatocellular Carcinoma

Development and Validation of Genome Instability-Associated lncRNAs to Predict Prognosis and Immunotherapy of Patients With Hepatocellular Carcinoma

Early Steps of Hepatitis B Life Cycle: From Capsid Nuclear Import to cccDNA Formation

A Five-Gene Signature Associated With DNA Damage Repair Molecular Subtype Predict Overall Survival for Hepatocellular Carcinoma

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