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Integrative Functional Genomics Implicated the Key T-/B-Cell Deficiency Regulator RAG1 in Transarterial Chemoembolization of Hepatocellular Carcinoma.

ABSTRACT: Transarterial chemoembolization (TACE) has significantly prolonged overall survival (OS) of unresectable hepatocellular carcinoma (HCC) patients. Unfortunately, there are still a portion of patients without therapeutic responses to TACE. Although genome-wide association studies identified multiple HCC susceptibility SNPs, it is still largely unclear how genome-wide identified functional SNPs impacting gene expression contribute to the prognosis of TACE-treated HCC patients. In this study, we developed an integrative functional genomics methodology to identify gene expression-related SNPs significantly contributing to prognosis of TACE-treated HCC patients across the whole genome. Employing integration of data from expression quantitative trait locus (eQTLs) analyses of The Cancer Genome Atlas (TCGA) liver hepatocellular carcinoma (LIHC) as well as the 1000 Genomes project, we successfully annotated 60 gene expression-related SNPs which are associated with OS of the TCGA patients. After genotyping these 60 SNPs in our TACE cohort, we identified four SNPs (rs12574873, rs12513391, rs34597395, and rs35624901) which are significantly associated with OS of HCC patients treated with TACE. For instance, multivariate Cox proportional hazards model indicated that the rs35624901 Deletion.Deletion (Del.Del) genotype carriers had markedly prolonged OS and a 55% decreased death risk compared with individuals with the GG genotype after TACE therapy (p = 8.3 × 10^-5). In support of this, the rs35624901 Del.Del genotype is correlated to higher expression of RAG1, a key T-/B-cell deficiency regulator. Our findings reported the first evidence supporting the prognostic value of four eQTL SNPs in TACE-treated HCC patients. Importantly, our data implicated that antitumor immunity might contribute to TACE efficiency for unresectable HCC patients.

SUBMITTER: Xu Y

PROVIDER: S-EPMC8502842 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:AimsThe purpose of the present study was to compare the efficacies of transarterial chemoembolization (TACE) combined with sorafenib versus TACE monotherapy for treating patients with advanced hepatocellular carcinoma (HCC).MethodsWe enrolled 321 patients and selected 280 with advanced HCC (Barcelona Clinic Liver Cancer stage C) who underwent TACE therapy between February 2009 and February 2013. TACE alone (monotherapy group) was administered to 198 patients (70.7%), and the remaining 82 (29.3%) underwent repeat combined TACE and sorafenib therapy (combined group). To minimize selection bias, these latter 82 patients were matched using propensity-score matching at a 1∶2 ratio with 164 patients who received TACE monotherapy. The primary endpoints were overall survival (OS) and related subgroup analysis. The secondary endpoints were time to progression (TTP) and treatment-related adverse events.ResultsOf the respective patients in the combined and monotherapy groups, 64.6% and 49.2% had vascular invasion, 87.8% and 91.1% had extrahepatic metastasis, and 54.3% and 47.1% had both. In the propensity-score-matched cohort, the OS survival of the combined group was significantly higher compared with the monotherapy group (7.0 months vs. 4.9 months, respectively, P = 0.003). The TTP was significantly longer in the combined group (2.6 months vs. 1.9 months, respectively, P = 0.001). Subgroup analysis showed that the outcomes of patients with advanced HCC without main portal vein invasion who were treated with combined therapy were significantly better compared with those who received monotherapy (P<0.05). Univariate and subsequent multivariate analyses revealed that the addition of sorafenib was an independent predictor of favorable OS and TTP (adjusted hazard ratios, 0.63 and 0.62, respectively; P<0.05 for both).ConclusionSorafenib plus TACE was more effective than TACE monotherapy for treating patients with advanced HCC without main portal vein invasion. Future trials with larger samples are required to validate these preliminary findings.

Project description:BackgroundThe combination of tyrosine kinase inhibitors (TKIs) and transarterial chemoembolization (TACE) fulfills an important role in the treatment of unresectable hepatocellular carcinoma (uHCC). Among the combination therapies, both lenvatinib and sorafenib combined with TACE are recommended as first-¬line treatments for uHCC. However, at present, limited data are available concerning the efficacy and safety of these two combination therapies in uHCC.MethodsA detailed systematic search for studies on lenvatinib plus TACE (LEN+TACE) and sorafenib plus TACE (SOR+TACE) was conducted in the online databases PubMed, Embase and The Cochrane Library. The outcome data including overall survival (OS), progression free survival (PFS), time to progression (TTP), tumor response and adverse events (AEs), were independently extracted by two authors in a standardized way.ResultsOne randomized controlled trial and five cohort studies with 598 patients (LEN+TACE: 261, SOR+TACE: 337) were included in the meta-analysis. A higher rate of odds ratio (OR) for the objective response rate (ORR) [OR: 3.63; 95% confidence intervals (95% CI): 1.89-6.95; I squared statistic (I2) = 57%, P < 0.001] and disease control rate (DCR) (OR: 3.78; 95% CI: 2.00-7.16; I2 = 52%, P = 0.0001) were observed in the LEN+SOR group compared with the SOR+TACE group. The LEN+TACE group also had significant longer OS [hazard ratio (HR): 0.67; 95% CI: 0.52-0.85; I2 = 1%, P = 0.001], PFS (HR: 0.49; 95% CI: 0.38-0.62; I2 = 0%, P? 0.001) and TTP (HR: 0.62; 95% CI: 0.45-0.84; I2 = 0%, P = 0.002) compared with the SOR+TACE group. The incidence of hypertension (OR: 3.05; 95% CI: 1.45-6.39; P = 0.003) and proteinuria (OR: 5.25; 95% CI: 1.73-15.89; P = 0.003) were significantly higher in the LEN+TACE group than SOR+TACE group, while LEN+TACE group exhibited a lower rate of hand-foot-skin reaction (HFSR) (OR: 0.51; 95% CI: 0.27-0.95; P = 0.03) compared with the SOR+TACE group.ConclusionThe combination therapy of LEN+TACE showed significant superiority compared with SOR+TACE in terms of its efficacy for patients with uHCC. SOR+TACE should be recommended as a replacement therapy when serious AEs occur during the administration of LEN+TACE as the combination therapy.

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Integrative Functional Genomics Implicated the Key T-/B-Cell Deficiency Regulator RAG1 in Transarterial Chemoembolization of Hepatocellular Carcinoma.

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