Exon 2 deletion splice variant of gamma-glutamyl carboxylase causes des-gamma-carboxy prothrombin production in hepatocellular carcinoma cell lines.
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ABSTRACT:
SUBMITTER: Ueda N
PROVIDER: S-EPMC5527806 | biostudies-other | 2008 Oct
REPOSITORIES: biostudies-other
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| S-EPMC5077674 | biostudies-literature
Project description:BACKGROUND & AIMS:The outcome of patients with hepatocellular carcinoma (HCC) remains poor because of late diagnosis. The aim of this study was to compare the accuracy of alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) in the early diagnosis of HCC. METHODS:Among 1031 patients randomized in the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C) Trial, a nested case-control study of 39 HCC cases (24 early stage) and 77 matched controls was conducted to compare the performance of AFP and DCP. Testing was performed on sera from 12 months prior (month -12) to the time of HCC diagnosis (month 0). RESULTS:The sensitivity and specificity of DCP at month 0 was 74% and 86%, respectively, at a cutoff of 40 mAU/mL and 43% and 100%, respectively, at a cutoff of 150 mAU/mL. The sensitivity and specificity of AFP at month 0 was 61% and 81% at a cutoff of 20 ng/mL and 22% and 100% at a cutoff of 200 ng/mL. At month -12, the sensitivity and specificity at the low cutoff was 43% and 94%, respectively, for DCP and 47% and 75%, respectively, for AFP. Combining both markers increased the sensitivity to 91% at month 0 and 73% at month 12, but the specificity decreased to 74% and 71%, respectively. Diagnosis of early HCC was triggered by surveillance ultrasound in 14, doubling of AFP in 5, and combination of tests in 5 patients. CONCLUSIONS:Biomarkers are needed to complement ultrasound in the detection of early HCC, but neither DCP nor AFP is optimal.
| S-EPMC2819612 | biostudies-literature
Project description:Background and aimsAssessing aggressive biology at early-stage hepatocellular carcinoma (HCC) diagnosis remains challenging. Alpha-fetoprotein (AFP) is the only clinical biomarker of aggressive HCC. In this study, AFP, Lens culinaris agglutinin-reactive AFP (AFP-L3), and des-γ-carboxy prothrombin (DCP) were measured at diagnosis prior to transplant evaluation and first cycle liver-directed therapy (LDT).MethodsThe prospective cohort included 207 patients who received LDT as a bridge/downstage to transplant or definitive treatment plan between 2016 and 2022. Plasma AFP, AFP-L3, and DCP levels were measured at diagnosis and analyzed with other factors associated with treatment response and time-to-progression.ResultsBiomarker phenotyping revealed 41% were triple negative, 30% expressed multiple biomarkers, and 12% express all 3 biomarkers. The biomarker profile was associated with target/overall response rate and time-to-progression (P < .001). Profiling stratified 1-year progression risk in nontransplant candidates, driven by coexpression of AFP and DCP in multivariate analysis controlling for tumor burden and staging.ConclusionThe biomarker panel at diagnosis established prognosis for LDT response and stratified 1-year HCC progression risk. AFP, AFP-L3, and DCP profiling isolated aggressive HCC biology at diagnosis and may have important implications in post-LDT surveillance and transplant wait time.
| S-EPMC11308544 | biostudies-literature
Project description:Background/aimsAlpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) have been used as diagnostic tools for hepatocellular carcinoma (HCC). However, prediction of outcome using AFP and DCP has not been elucidated. We investigated the clinical role of AFP and DCP as predictors of treatment outcome in patients with HCC undergoing trans-arterial chemoembolization (TACE).MethodsBetween January 2003 and December 2005, we enrolled 115 treatment-naïve patients who received TACE as an initial treatment modality. An AFP or DCP response was defined as a reduction of more than 50% from the baseline level 1 month after TACE. Patients with AFP < 20 ng/mL or DCP < 20 mAU/mL were excluded.ResultsThe median age was 59 years and the male gender predominated (n = 81, 70.4%). AFP and DCP response was identified in 91 (79.1%) and 77 (66.9%) patients after TACE. Although progression-free survival (PFS) did not differ according to AFP response (P = 0.150), AFP responders showed significantly better overall survival (OS) than non-responders (34.9 vs. 13.2 months; P = 0.002). In contrast, DCP response did not influence either PFS or OS (all P > 0.05). Multivariate analyses showed that gamma-glutamyltranspeptidase and baseline AFP were predictors of PFS (all P < 0.05) and that male gender, the presence of liver cirrhosis, baseline DCP, number of measurable tumors and AFP response were independent predictors of OS (all P < 0.05).ConclusionsAFP response and higher baseline DCP level are significant predictors of OS in treatment-naïve patients with HCC receiving TACE who showed pretreatment elevation of both AFP and DCP.
| S-EPMC3545962 | biostudies-literature
Project description:Via generation of vitamin K-dependent proteins, gamma-glutamyl carboxylase (GGCX) plays a critical role in the vitamin K cycle. Single nucleotide polymorphisms (SNPs) in GGCX, therefore, may affect dosing of the vitamin K antagonist, warfarin. In a multi-centered, cross-sectional study of 985 patients prescribed warfarin therapy, we genotyped for two GGCX SNPs (rs11676382 and rs12714145) and quantified their relationship to therapeutic dose. GGCX rs11676382 was a significant (p=0.03) predictor of residual dosing error and was associated with a 6.1% reduction in warfarin dose (95% CI: 0.6%-11.4%) per G allele. The prevalence was 14.1% in our predominantly (78%) Caucasian cohort, but the overall contribution to dosing accuracy was modest (partial R2 = 0.2%). GGCX rs12714145 was not a significant predictor of therapeutic dose (p = 0.26). GGCX rs11676382 is a statistically significant predictor of warfarin dose, but the clinical relevance is modest. Given the potentially low marginal cost of adding this SNP to existing genotyping platforms, we have modified our non-profit website (www.WarfarinDosing.org) to accommodate knowledge of this variant.
| S-EPMC2949522 | biostudies-literature
Project description:BackgroundSerum des-γ-carboxy prothrombin (DCP) is a hepatocellular carcinoma (HCC) tumor marker that can be used to assess patient prognosis. Since the value of DCP in predicting the prognosis of hepatocellular carcinoma patients treated with transarterial chemotherapy remains controversial, we performed a meta-analysis of previous clinical studies.MethodsA systematic literature search was performed using PubMed, the MEDLINE database, EMBASE, and the Cochrane Library in accordance with the PRISMA guidelines. The hazard ratio (HR) with 95% confidence interval (CI) was used to estimate the effect size.ResultsSix respective cohort studies including a total of 943 cases were identified. The pooled results showed that low DCP was associated with a favorable overall survival (OS)(HR 0.653, 95% CI 0.444-0.960), and DCP response was associated with increased OS (HR 0.387,95% CI 0.215-0.697) and progression-free survival (PFS) (HR 0.42,95% CI 0.23-0.74) in HCC patients treated with transarterial chemotherapy.ConclusionsDCP values in HCC patients undergoing hepatic arterial chemotherapy seem to be associated with OS and PFS. Thus, monitoring DCP values and observing the DCP response should be part of the management of patients undergoing transarterial chemotherapy.
| S-EPMC6857949 | biostudies-literature
Project description:The biomarkers α-fetoprotein (AFP), Lens culinaris agglutinin-reactive AFP fraction (AFP-L3), and des-γ-carboxy prothrombin (DCP) have emerging implications in hepatocellular carcinoma (HCC) surveillance, overall prognosis, and post-surgical recurrence risk. This retrospective study investigated treatment and bridge to liver transplant (LT) prognosis associated with AFP, AFP-L3%, and DCP biomarker profiles prior to liver-directed therapy (LDT). In a 140-patient cohort, each biomarker was associated with HCC progression risk using the established thresholds of AFP > 20 ng/mL, AFP-L3 > 15%, and DCP > 7.5 ng/mL. Over 60% of the cohort expressed at least one biomarker at baseline. Although most biomarker-positive patients expressed the clinical standard AFP (57/87), only 32% were positive for AFP alone. Biomarker accumulation increased HCC progression risk but was not associated with demographic factors or preserved liver function. Biomarker triple negative patients had smaller index HCC (p = 0.003), decreased multifocal burden (p = 0.010), and a higher objective response rate (ORR, 62% compared to 46%, p = 0.011). Expressing all three biomarkers at baseline was associated with dismal first-line ORR (12%) with a median time to progression (TTP) of only 181 days post-LDT. Patients with triple negative status for the HCC biomarkers AFP, AFP-L3%, and DCP have the highest first-line ORR with < 5% HCC progression 1-year post-LDT. Biomarker profiling can establish baseline prognosis for identifying optimal bridge to LT and downstaging to LT candidates with triple negative biomarker status and providing an ideal post-LDT target as a compliment to radiographic response.
| S-EPMC8507524 | biostudies-literature
Project description:An efficient serum marker for hepatocellular carcinoma (HCC) is currently lacking and requires intensive exploration. We aimed to evaluate the performance of des-gamma-carboxy prothrombin (DCP) for identifying hepatitis B virus-related HCC in a large, multicentre study in China. A total of 1034 subjects in three cohorts (A, B, and C) including HCC and various non-HCC controls were enrolled from 4 academic medical centers in China from January 2011 to February 2014. Blind parallel detections were conducted for DCP and AFP. The area under the receiver operating characteristic curve (AUC) was used to evaluate the diagnostic efficacies. In cohort A, which comprised 521 subjects, including patients with HCC, liver metastasis, liver cirrhosis (LC), and liver hemangiomas as well as healthy controls (HCs), the accuracy of DCP for distinguishing HCC from various controls was 6.2-9.7% higher than that of AFP. In cohort B, which comprised 447 subjects, including patients with HCC, LC, and chronic hepatitis B as well as HC, the accuracy of DCP was further elevated (12.3-20.67% higher than that of AFP). The superiority of DCP to AFP was more profound in the surveillance of early HCC [AUC 0.837 (95% CI: 0.771-0.903) vs. 0.650 (0.555-0.745)] and AFP-negative HCC [AUC: 0.856 (0.798-0.914)] and in discriminating HCC from LC (accuracy: 92.9% vs.64.71%). Higher DCP levels were associated with worse clinical behaviors and shorter disease-free survival. DCP not only is complementary to AFP in identifying AFP-negative HCC and in excluding AFP-positive non-HCC (liver cirrhosis), but also demonstrates improved performance in HCC surveillance, early diagnosis, treatment response and recurrence monitoring in the HBV-related population.
| S-EPMC4829182 | biostudies-literature
Project description:Essentials A carboxylase mutation that impairs splicing to delete exon 2 sequences was previously reported. We found that the mutant was inactive for vitamin K-dependent (VKD) protein carboxylation. An incomplete splicing defect likely accounts for VKD clotting activity observed in the patient. The results indicate the importance of proper carboxylase embedment in the membrane for function.BackgroundMutations in the γ-glutamyl carboxylase (GGCX), which is required for vitamin K-dependent (VKD) protein activation, can result in vitamin K clotting factor deficiency (VKCFD1). A recent report described a VKCFD1 patient with a homozygous carboxylase mutation that altered splicing and deleted exon 2 (Δ2GGCX). Only Δ2GGCX RNA was observed in the patient.ObjectivesLoss of exon 2 results in the deletion of carboxylase sequences thought to be important for membrane topology and consequent function. Carboxylase activity is required for life, and we therefore tested whether the Δ2GGCX mutant is active.MethodsHEK 293 cells were edited by the use of CRISPR-Cas9 to eliminate endogenous carboxylase. Recombinant wild-type GGCX and recombinant Δ2GGCX were then expressed and tested for carboxylation of the VKD protein factor IX. A second approach was used to monitor carboxylation biochemically, using recombinant carboxylases expressed in insect cells that lack endogenous carboxylase.Results and conclusionsΔ2GGCX activity was undetectable in both assays, which is strikingly different from the low levels of carboxylase activity observed with other VKCFD1 mutants. The similarity in clotting function between patients with Δ2GGCX and these mutations must therefore arise from a novel mechanism. Low levels of properly spliced carboxylase RNA that produce full-length protein would not have been observed in the previous study. The results suggest that the splicing defect is incomplete. Δ2GGCX RNA has been detected in normal human liver, and has been designated carboxylase isoform 2; however, Δ2GGCX protein was not observed in normal human liver. The lack of activity and protein expression suggest that isoform 2 is not physiologically relevant to normal VKD protein carboxylation.
| S-EPMC7181818 | biostudies-literature
Project description:3-Methylcrotonyl-CoA carboxylase (MCC) deficiency is an autosomal recessive disorder of leucine catabolism. MCC is a heteromeric mitochondrial enzyme composed of biotin-containing alpha (MCCA) and smaller beta (MCCB) subunits encoded by MCCA and MCCB, respectively. We report studies of the c.1054G-->A mutation in exon 11 of MCCB detected in the homozygous state in a patient with MCC deficiency. Sequence analysis of MCCB cDNA revealed two overlapping transcripts, one containing the normal 73 bp of exon 11 including the missense mutation c.1054G-->A (p.G352R), the other with exon 11 replaced by a 64-bp sequence from intron 10 (cryptic exon 10a) that maintains the reading frame and is flanked by acceptable splice consensus sites. In expression studies, we show that both transcripts lack detectable MCC activity. Western blot analysis showed slightly reduced levels of MCCB using the transcript containing the missense mutation, whereas no MCCB was detected with the transcript containing the cryptic exon 10a. Analysis of the region harboring the mutation revealed that the c.1054G-->A mutation is located in an exon splice enhancer sequence. Using MCCB minigene constructs to transfect MCCB-deficient fibroblasts, we demonstrate that the reduction in utilization of exon 11 associated with the c.1054G-->A mutation is due to alteration of this exon splice enhancer. Further, we show that optimization of the weak splice donor site of exon 11 corrects the splicing defect. To our knowledge, this is the first demonstration of a point mutation disrupting an exon splice enhancer that causes exon skipping along with utilization of a cryptic exon.
| S-EPMC2781441 | biostudies-literature