Analysis of mutations in DNA damage repair pathway gene in Chinese patients with hepatocellular carcinoma.
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ABSTRACT:
SUBMITTER: Li J
PROVIDER: S-EPMC9296649 | biostudies-literature | 2022 Jul
REPOSITORIES: biostudies-literature
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Analysis of mutations in DNA damage repair pathway gene in Chinese patients with hepatocellular carcinoma.
Li Jiarong J Li Nianfeng N Azhar Muhammad Salman MS Liu Ling L Wang Liheng L Zhang Qi Q Sheng Langqing L Wang Jianhua J Feng Sijia S Qiu Qixuan Q Xiao Yao Y
Scientific reports 20220719 1
The incidence of hepatocellular carcinoma (HCC) has increased in these years. DNA damage repair (DDR) pathway is required in response to DNA damage Gene mutations in DDR pathway play an important role in different stages of tumorigenesis and development. Based on the importance of DDR pathway in precision therapy of multiple cancers, we analyzed DDR gene mutations in Chinese patients with HCC. The results showed that (tumor mutation burden) TMB was significantly higher in HCC patients who carrie ...[more]
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Project description:DNA repair pathways have been associated with variability in hepatocellular carcinoma (HCC) clinical outcomes, but the mechanism through which DNA repair varies as a function of liver regeneration and other HCC characteristics is poorly understood. We curated a panel of 199 genes representing 15 DNA repair pathways to identify DNA repair expression classes and evaluate their associations with liver features and clinicopathologic variables in The Cancer Genome Atlas (TCGA) HCC study. We identified two groups in HCC, defined by low or high expression across all DNA repair pathways. The low-repair group had lower grade and retained the expression of classical liver markers, whereas the high-repair group had more clinically aggressive features, increased p53 mutant-like gene expression, and high liver regenerative gene expression. These pronounced features overshadowed the variation in the low-repair subset, but when considered separately, the low-repair samples included three subgroups: L1, L2, and L3. L3 had high DNA repair expression with worse progression-free (HR 1.24, 95% CI 0.81-1.91) and overall (HR 1.63, 95% CI 0.98-2.71) survival. High-repair outcomes were also significantly worse compared with the L1 and L2 groups. HCCs vary in DNA repair expression, and a subset of tumors with high regeneration profoundly disrupts liver biology and poor prognosis.
| S-EPMC9454479 | biostudies-literature
Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC) is a fatal disease with molecular heterogeneity, inducing differences in biological behavior, and therapeutic strategy. NGS profiles of pathogenic alterations in the Chinese PDAC population are limited. We conducted a retrospective study to investigate the predictive role of DNA damage repair (DDR) mutations in precision medicine.MethodsThe NGS profiles were performed on resected tissues from 195 Chinese PDAC patients. Baseline clinical or genetic characteristics and survival status were collected. The Kaplan-Meier survival analyses were performed by the R version 3.6.1.ResultsThe main driver genes were KRAS, TP53, CDKN2A, and SMAD4. Advanced patients with KRAS mutation showed a worse OS than KRAS wild-type (p = 0.048). DDR pathogenic deficiency was identified in 30 (15.38%) of overall patients, mainly involving BRCA2 (n = 9, 4.62%), ATM (n = 8, 4.10%) and RAD50 genes (n = 3, 1.54%). No significance of OS between patients with or without DDR mutations (p = 0.88). But DDR mutation was an independent prognostic factor for survival analysis of advanced PDAC patients (p = 0.032). For DDR mutant patients, treatment with platinum-based chemotherapy (p = 0.0096) or olaparib (p = 0.018) respectively improved the overall survival. No statistical difference between tumor mutation burden (TMB) and DDR mutations was identified. Treatment of PD-1 blockades did not bring significantly improved OS to DDR-mutated patients than the naive DDR group (p = 0.14).ConclusionsIn this retrospective study, we showed the role of germline and somatic DDR mutation in predicting the efficacy of olaparib and platinum-based chemotherapy in Chinese patients. However, the value of DDR mutation in the prediction of hypermutation status and the sensitivity to the PD-1 blockade needed further investigation.
| S-EPMC8273977 | biostudies-literature
Project description: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.
| S-EPMC8811360 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed cancers and a leading cause of cancer-related mortality worldwide, but its pathogenesis remains largely unknown. Nevertheless, genomic instability has been recognized as one of the facilitating characteristics of cancer hallmarks that expedites the acquisition of genetic diversity. Genomic instability is associated with a greater tendency to accumulate DNA damage and tumor-specific DNA repair defects, which gives rise to gene mutations and chromosomal damage and causes oncogenic transformation and tumor progression. Histone deacetylases (HDACs) have been shown to impair a variety of cellular processes of genome stability, including the regulation of DNA damage and repair, reactive oxygen species generation and elimination, and progression to mitosis. In this review, we provide an overview of the role of HDAC in the different aspects of DNA repair and genome instability in HCC as well as the current progress on the development of HDAC-specific inhibitors as new cancer therapies.
| S-EPMC9647118 | biostudies-literature
Project description:The heterogeneity of hepatocellular carcinoma (HCC) poses a challenge for accurate prognosis prediction. DNA damage repair genes (DDRGs) have an impact on a wide range of malignancies. However, the relevance of these genes in HCC prognosis has received little attention. In this study, we aimed to develop a prognostic signature to identify novel therapy options for HCC. We acquired mRNA expression profiles and clinical data for HCC patients from The Cancer Genome Atlas (TCGA) database. A polygenic prognostic model for HCC was constructed using selection operator Cox analysis and least absolute shrinkage. The model was validated using International Cancer Genome Consortium (ICGC) data. Overall survival (OS) between the high-risk and low-risk groups was compared using Kaplan‒Meier analysis. Independent predictors of OS were identified through both univariate and multivariate Cox analyses. To determine immune cell infiltration scores and activity in immune-related pathways, a single-sample gene set enrichment analysis was performed. The protein and mRNA expression levels of the prognostic genes between HCC and normal liver tissues were also examined by immunohistochemistry (IHC), immunofluorescence (IF) and quantitative real-time PCR (qRT-PCR). A novel ten-gene signature (CHD1L, HDAC1, KPNA2, MUTYH, PPP2R5B, NEIL3, POLR2L, RAD54B, RUVBL1 and SPP1) was established for HCC prognosis prediction. Patients in the high-risk group had worse OS than those in the low-risk group. Receiver operating characteristic curve analysis confirmed the predictive ability of this prognostic gene signature. Multivariate Cox analysis showed that the risk score was an independent predictor of OS. Functional analysis revealed a strong association with cell cycle and antigen binding pathways, and the risk score was highly correlated with tumor grade, tumor stage, and types of immune infiltrate. High expression levels of the prognostic genes were significantly correlated with increased sensitivity of cancer cells to antitumor drugs. IHC, IF and qRT-PCR all indicated that the prognostic genes were highly expressed in HCC relative to normal liver tissue, consistent with the results of bioinformatics analysis. Ten DDRGs were utilized to create a new signature for identifying the immunological state of HCC and predicting prognosis. In addition, blocking these genes could represent a promising treatment.
| S-EPMC10624694 | biostudies-literature
Project description:Herein, we reported mutations in five DNA Damage Repair (DDR) i.e., TP53, ATR, ATM, CHEK1 and CHEK2 involved in OSCC using NG-WES and their analysis using bioinformatics tools. Out of 42 identified mutations, 16.7% are reported for the 1st time. A total of 28 nonsynonymous SNVs are identified. TP53 harbored the highest number of mutations followed by ATM, ATR, CHEK1 and CHEK2. Nine mutations (TP53p.R43H, TP53p.L125Q, TP53p.R116Q, TP53p.C110Y, TP53p.L62F, ATRp.H120Y, ATMp.P1054R, ATMp.D1853V, ATMp.T2934N) were predicted highly pathogenic. SAAFEQ-SEQ predicted destabilizing effects for all mutations, while ISPRED-SEQ identified 09 IS mutations, 07 on TP53, 01 in ATR and 01 in CHEK1 with no IS mutations predicted for ATM and CHEK2. Among the IS mutations, only SNVs were used in MDS simulations. The gyration radius for all IS SNVs was larger for mutant as compared to the wild type indicating perturbed folding behavior of the mutant proteins. Structural deviations across the carbon back bone were noted by RMSD for mutant and wild type. The TP53 IS mutations include TP53p.R116Q, TP53 p.C110Y, TP53p.R43H, TP53p.E214X, TP53p.R210X, TP53 p.C110Afs*5 and TP53 p,S108Ffs*23 whereas ATR and CHEK1 IS mutations consist of ATRp.M1932T and CHEK1p.E76Kfs*21. ConSurf analysis revealed four SNVs with a high conservation score (9) on TP53 and ATM. TP53p.P33R was predominantly associated with moderately differentiated tumors (84.60%), naswar users (86.60%) and positive family history of cancer (91.60%). The TP53p.P33R, ATRp.M211T and CHEK1p.I437V mutations were found recurrently in 21/27 (77.7%), 20/27 (74.04%), and 27/27 (100%) patients, suggesting its potential biomarker applications in local screening.
| S-EPMC11885471 | biostudies-literature
Project description:Background: Nowadays, although the cause of hepatocellular carcinoma (HCC) mortality and recurrence remains at a high level, the 5-year survival rate is still very low. The DNA damage response and repair (DDR) pathway may affect HCC patients' survival by influencing tumor development and therapeutic response. It is necessary to identify a prognostic DDR-related gene signature to predict the outcome of patients. Methods: Level 3 mRNA expression and clinical information were extracted from the TCGA website. The GSE14520 datasets, ICGC-LIRI datasets, and a Chinese HCC cohort were served as validation sets. Univariate Cox regression analysis and LASSO-penalized Cox regression analysis were performed to construct the DDR-related gene pair (DRGP) signature. Kaplan-Meier survival curves and time-dependent receiver operating characteristic (ROC) analysis curves were calculated to determine the predictive ability of this prognostic model. Then, a prognostic nomogram was established to help clinical management. We investigated the difference in biological processes between HRisk and LRisk by conducting several enrichment analyses. The TIDE algorithm and R package "pRRophetic" were applied to estimate the immunotherapeutic and chemotherapeutic response. Results: We constructed the prognostic signature based on 23 DDR-related gene pairs. The patients in the training datasets were divided into HRisk and LRisk groups at median cut-off. The HRisk group had significantly poorer OS than the LRisk group, and the signature was an independent prognostic indicator in HCC. Furthermore, a nomogram of the riskscore combined with TNM stage was constructed and detected by the calibration curve and decision curve. The LRisk group was associated with higher expression of HBV oncoproteins and metabolism pathways, while DDR-relevant pathways and cell cycle process were enriched in the HRisk group. Moreover, patients in the LRisk group may be more beneficial from immunotherapy. We also found that TP53 gene was more frequently mutated in the HRisk group. As for chemotherapeutic drugs commonly used in HCC, the HRisk group was highly sensitive to 5-fluorouracil, while the LRisk group presented with a significantly higher response to gefitinib and gemcitabine. Conclusion: Overall, we developed a novel DDR-related gene pair signature and nomogram to assist in predicting survival outcomes and clinical treatment of HCC patients. It also helps understand the underlying mechanisms of different DDR patterns in HCC.
| S-EPMC9038539 | biostudies-literature
Project description:BackgroundThe incidence and mortality of hepatocellular carcinoma (HCC) are globally on the rise. Dihydrotanshinone I, a natural product isolated from Salvia miltiorrhiza Bunge, has attracted extensive attention in recent years for its anti-tumour proliferation efficiency.MethodsCell proliferations in hepatoma cells (Huh-7 and HepG2) were evaluated by MTT and colony formation assays. Immunofluorescence (IF) of 53BP1 and flow cytometry analysis were performed to detect DNA damage and cell apoptosis. Furthermore, network pharmacological analysis was applied to explore the potential therapeutic targets and pathway of dihydrotanshinone I.ResultsThe results showed that dihydrotanshinone I effectively inhibited the proliferation of Huh-7 and HepG2 cells. Moreover, dihydrotanshinone I dose-dependently induced DNA-damage and apoptosis in vitro. Network pharmacological analysis and molecular simulation results indicated that EGFR might be a potential therapeutic target of dihydrotanshinone I in HCC. Collectively, our findings suggested that dihydrotanshinone I is a novel candidate therapeutic agent for HCC treatment.
| S-EPMC10019332 | biostudies-literature
Project description:Immune checkpoint inhibitors(ICIs) that activate tumor-specific immune responses bring new hope for the treatment of hepatocellular carcinoma(HCC). However, there are still some problems, such as uncertain curative effects and low objective response rates, which limit the curative effect of immunotherapy. Therefore, it is an urgent problem to guide the use of ICIs in HCC based on molecular typing. We downloaded the The Cancer Genome Atlas-Liver hepatocellular carcinoma(TCGA-LIHC) and Mongolian-LIHC cohort. Unsupervised clustering was applied to the highly variable data regarding expression of DNA damage repair(DDR). The CIBERSORT was used to evaluate the proportions of immune cells. The connectivity map(CMap) and pRRophetic algorithms were used to predict the drug sensitivity. There were significant differences in DDR molecular subclasses in HCC(DDR1 and DDR2), and DDR1 patients had low expression of DDR-related genes, while DDR2 patients had high expression of DDR-related genes. Of the patients who received traditional treatment, DDR2 patients had significantly worse overall survival(OS) than DDR1 patients. In contrast, of the patients who received ICIs, DDR2 patients had significantly prolonged OS compared with DDR1 patients. Of the patients who received traditional treatment, patients with high DDR scores had worse OS than those with low DDR scores. However, the survival of patients with high DDR scores after receiving ICIs was significantly higher than that of patients with low DDR scores. The DDR scores of patients in the DDR2 group were significantly higher than those of patients in the DDR1 group. The tumor microenvironment(TME) of DDR2 patients was highly infiltrated by activated immune cells, immune checkpoint molecules and proinflammatory molecules and antigen presentation-related molecules. In this study, HCC patients were divided into the DDR1 and DDR2 group. Moreover, DDR status may serve as a potential biomarker to predict opposite clinical prognosis immunotherapy and non-immunotherapy in HCC.
| S-EPMC8320764 | biostudies-literature
Project description:IntroductionAlthough next-generation sequencing (NGS) has brought insight into critical mutations or pathways (e.g., DNA damage sensing and repair) involved in the etiology of many cancers and has directed new screening, prevention, and therapeutic approaches for patients and families, it has only recently been used in malignant pleural mesotheliomas (MPMs).MethodsWe analyzed the blood samples from patients with MPM using the NGS platform MSK-IMPACT to explore cancer-predisposing genes. The loss-of-function variants or pathogenic entries were identified, and clinicopathologic information was collected.ResultsOf 84 patients with MPM, 12% (10 of 84) had pathogenic variants. Clinical characteristics were similar between cohorts, although patients with germline pathogenic variants were more likely to have more than two first-degree family members with cancer than those without germline mutations (40% versus 12%; Fisher's exact test, p < 0.05). Novel, deleterious variants in mesotheliomas included MutS homolog 3 (1% [one of 84]; 95% confidence interval [CI]: 0%-7%), breast cancer gene 1-associated ring domain 1 (1% [one of 84]; 95% CI: 0%-7%), and RecQ-like helicase 4 (2% [two of 84]; 95% CI: 0%-9%). Pathogenic variants previously reported on germline testing in patients with mesotheliomas were breast cancer gene 1-associated protein 1 (4% [three of 84]; 95% CI: 1%-10%), breast cancer gene 2 (1% [one of 84]; 95% CI: 0%-7%), and MRE11 homolog, double strand break repair nuclease (1% [one of 84]; 95% CI: 0%-7%). One patient (1% [one of 84]; 95% CI: 0%-7%) had a likely pathogenic alteration in SHQ1, H/ACA ribonucleoprotein assembly factor that has not been associated with a heritable susceptibility to cancer.ConclusionsOur study lends further support for the role of aberrations in DNA damage repair genes in the pathogenesis of MPMs and suggests that targeting the members of these pathways for screening and treatment warrants further study.
| S-EPMC7526793 | biostudies-literature