Background: Copper metabolism plays an important role in the tumor microenvironment, and cuproptosis is the last discovered programmed cell death process. However, the potential mechanism of cuproptosis in regulating the immune microenvironment of HCC remains unclear.Methods: A total of 716 HCC patients with complete mRNA expression and survival information were collected from three public HCC cohorts (TCGA-LIHC cohort, n = 370; GSE76427 cohort, n = 115; ICGC-LIRI cohort, n = 231). The unsupervised clustering analysis (NMF) was performed to identify three different cuproptosis-related subtypes. The univariate-Cox, lasso-Cox and multivariate-Cox regression analyses were performed to screen the cuproptosis related and construct the cuproptosis-related prognosis signature (Cu-PS). The immune cell infiltration was estimated by both CIBERSORT and MCPcounter algorithms.Results: This study identified three distinct cuproptosis-related metabolic patterns, which presented different pathway enrichment and immune cell infiltration. The Cu-PS, a 5-genes (C7, MAGEA6, HK2, CYP26B1 and EPO) signature, was significantly associated with TNM stage, tumor mutational burden (TMB), drugs sensitivity, and immunotherapies response.Conclusion: This study performed a multi-genetic analysis of cuproptosis-related genes and further explored the regulatory mechanism of cuproptosis in HCC. The Cu-PS might be a useful biomarker for predicting immunotherapy response and enhancing the diagnosis and treatment of HCC.
Background: Coronary disorders are recognized as the most common manifestation of fluoropyrimidine-related cardiotoxicity in clinical practice. However, there are limited and conflicting data on the incidence and profiles of fluoropyrimidine-related coronary disorders. In this meta-analysis, we aimed to systematically assess the incidence of all-grade and grade 3 or higher fluoropyrimidine-related coronary disorders, and further explore the factors that influence its occurrence.Methods: Studies reporting the fluoropyrimidine-related coronary disorders were retrieved from a systematic search of English literature in the PubMed, Web of Science, Medline, and Cochrane database from 1 Jan 2001, to 1 Jan 2022. The NIH assessment tool was used to evaluate the quality of each study. The data of basic study characteristics, treatment details, and results of coronary toxicities were extracted. According to the results of the heterogeneity test (I2 and p-value statistic), a random-effect model or fixed-effect model was selected for the pooled analysis of the incidence of adverse coronary events. Subgroup analysis was conducted to further explore the risks influencing the occurrence of fluoropyrimidine-related coronary disorders. The stability and publication bias of our results were evaluated by sensitivity analysis and Egger test, respectively.Results: A total of 63 studies were finally included in our pooled analysis, involving 25,577 patients. The pooled cumulative incidence of all-grade and grade 3 or higher coronary disorders was 2.75% (95% CI 1.89%–3.76%) and 1.00% (95% CI 0.62%–1.47%), respectively. The coronary disorders were most reported as myocardial ischemia (1.28%, 95% CI 0.42%–2.49%) and angina/chest pain (1.1%, 95% CI 0.54%–1.81%). Subgroup analysis revealed that studies in the female-only population seemed to have a lower incidence of fluoropyrimidine-related coronary disorders. The occurrence of adverse coronary events varied among different tumor types. Patients with esophageal cancer have the highest coronary toxicity (6.32%), while those with breast cancer have a relatively lower incidence (0.5%). Coronary disorders induced by 5-FU monotherapy are more frequent than that induced by capecitabine (3.31% vs. 1.21%, p < 0.01). Fluoropyrimidine combination therapy, whether combined with other chemotherapy drugs, targeted therapy drugs, or radiotherapy, significantly increased the incidence of coronary complications (p < 0.01).Conclusion: This meta-analysis has defined the incidence of fluoropyrimidine-related coronary disorders and depicted its epidemiological profiles for the first time, which may provide a reference for clinical practice in cancer management.
Background: Increasing evidence illustrated that m6A regulator-mediated modification plays a crucial role in regulating tumor immune and angiogenesis microenvironment. And the combination of immune checkpoint inhibitor and anti-angiogenic therapy has been approved as new first-line therapy for advanced HCC. This study constructed a novel prognosis signature base on m6A-mediated modification and explored the related mechanism in predicting immune and anti-angiogenic responses.Methods: Gene expression profiles and clinical information were collected from TCGA and GEO. The ssGSEA, MCPCOUNT, and TIMER 2.0 algorithm was used to Estimation of immune cell infiltration. The IC50 of anti-angiogenic drugs in GDSC was calculated by the “pRRophetic” package. IMvigor210 cohort and Liu et al. cohort were used to validate the capability of immunotherapy response. Hepatocellular carcinoma single immune cells sequencing datasets GSE140228 were collected to present the expression landscapes of 5 hub genes in different sites and immune cell subpopulations of HCC patients.Results: Three m6A clusters with distinct immune and angiogenesis microenvironments were identified by consistent cluster analysis based on the expression of m6A regulators. We further constructed a 5-gene prognosis signature (termed as m6Asig-Score) which could predict both immune and anti-angiogenic responses. We illustrated that high m6Asig-Score is associated with poor prognosis, advanced TNM stage, and high TP53 mutation frequency. Besides, the m6Asig-Score was negatively associated with immune checkpoint inhibitors and anti-angiogenic drug response. We further found that two of the five m6Asig-Score inner genes, B2M and SMOX, were associated with immune cell infiltration, immune response, and the sensitivity to sorafenib, which were validated in two independent immunotherapy cohorts and the Genomics of Drug Sensitivity in Cancer (GDSC) database.Conclusion: We constructed a novel prognosis signature and identified B2M and SMOX for predicting immune and anti-angiogenic efficacy in HCC, which may guide the combined treatment strategies of immunotherapy and anti-angiogenic therapy in HCC.
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