Serum alpha fetoprotein levels in Fanconi anaemia.
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ABSTRACT:
SUBMITTER: Alter BP
PROVIDER: S-EPMC6383512 | biostudies-literature | 2019 Mar
REPOSITORIES: biostudies-literature
Publications
Serum alpha fetoprotein levels in Fanconi anaemia.
Alter Blanche P BP Giri Neelam N
British journal of haematology 20180820 6
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Project description:Background & aimsUltrasound (US)-based screening has been recommended for patients with an increased risk of hepatocellular carcinoma (HCC). US analysis, however, is limited in patients who are obese or have small tumors. The addition of serum level of α-fetoprotein (AFP) measurements to US analysis can increase detection of HCC. We analyzed data from patients with chronic liver disease, collected over 15 years in an HCC surveillance program, to develop a model to assess risk of HCC.MethodsWe collected data from 3450 patients with chronic liver disease undergoing US surveillance in Japan from March 1998 through April 2014, and followed them up for a median of 8.83 years. We performed longitudinal discriminant analysis of serial AFP measurements (median number of observations/patient, 56; approximately every 3 months) to develop a model to determine the risk of HCC. We validated the model using data from 2 cohorts of patients with chronic liver disease in Japan (404 and 2754 patients) and 1 cohort in Scotland (1596 patients).ResultsHCC was detected in 413 patients (median tumor diameter, 1.8 cm), during a median follow-up time of 6.60 years. In the development data set, the model identified patients who developed HCC with an area under the curve of 0.78; it correctly identified 74.3% of patients who did develop HCC, and 72.9% of patients who did not. Overall, 73.1% of patients were classified correctly. The model could be used to assign patients to a high-risk group (27.5 HCCs/1000 patient-years) vs a low-risk group (4.9 HCCs/1000 patient-years). A similar performance was observed when the model was used to assess patients with cirrhosis. Analysis of the validation cohorts produced similar results.ConclusionsWe developed and validated a model to identify patients with chronic liver disease who are at risk for HCC based on change in serum AFP level over time. The model could be used to assign patients to high-risk vs low-risk groups, and might be used to select patients for surveillance.
| S-EPMC7611145 | biostudies-literature
Project description:AimsThe embryonic-like stem cell origin of infantile hemangioma (IH) and the observed elevated serum levels of alpha-fetoprotein (AFP) in patients with hepatic IH led us to investigate if this tumor was the source of AFP.Materials and methodsWe measured serial serum levels of AFP in patients with problematic proliferating IH treated with surgical excision or propranolol treatment. We also investigated the expression of AFP in extrahepatic IH samples using immunohistochemical staining, mass spectrometry, NanoString gene expression analysis, and in situ hybridization.ResultsSerum levels of AFP normalized following surgical excision or propranolol treatment. Multiple regression analysis for curve fittings revealed a different curve compared to reported normal values in the general populations. AFP was not detected in any of the IH samples examined at either the transcriptional or translational levels.ConclusionThis study demonstrates the association of proliferating IH with elevated serum levels of AFP, which normalized following surgical excision or propranolol treatment. We have shown that IH is not the direct source of AFP. An interaction between the primitive mesoderm-derived IH and the endogenous endodermal tissues, such as the liver, via an intermediary, may explain the elevated serum levels of AFP in infants with extrahepatic IH.
| S-EPMC4746268 | biostudies-literature
Project description:Serum α-fetoprotein (AFP), a well-established biomarker for hepatocellular carcinoma (HCC), increases the sensitivity of ultrasound-based surveillance programs for early stage HCC detection.1,2 Multiple factors, including tumor burden, can affect AFP levels in patients with HCC.3 Nontumoral factors, such as race/ethnicity and liver disease etiology, are also known to be associated with elevated AFP.3 With the increasing trend of earlier stage HCC detection and shift from viral to nonviral etiology, we hypothesized that AFP level at HCC diagnosis would decrease in the United States.
| S-EPMC8837708 | biostudies-literature
Project description:The Fanconi Anaemia (FA) pathway resolves replication fork-stalling inter-strand crosslinks (ICLs) and is mutated in Fanconi anaemia. FA is a rare recessive chromosomal instability syndrome, resulting in hypersensitivity to DNA-crosslinkers, and particularly disadvantageous for stem cell growth and maintenance. FA individuals have an increased risk to haematological malignancies (AML) and head-and-neck squamous cell carcinomas (HNSCC), often very aggressive. Systemic intolerance due to somatic cell hypersensitivity to standard chemo-radio-therapy in patients limits treatment options in FA-HNSCC underscoring an urgent, unmet need to develop novel therapeutic strategies. Here, we performed unbiased functional genomic siRNA screens to unveil genetic interactions that are synthetic lethal with FA pathway deficiency, in a panel of patient-derived, FA-core-complex mutated HNSCC cell lines. We identified RBBP9, LAMTOR2, PSMB2 and PSMC1, among others, as potential FA-HNSCC-specific hits. We demonstrate that RBBP9, a poorly characterized serine hydrolase is synthetically lethal in FA-defective HNSCC and crucial for FA-HNSCC survival. RBBP9 interaction partners are identified in a RBBP9-FLAG IP-MS experiment.
2022-10-27 | PXD026545 | Pride
Project description:Liver metastasis in gastric cancer is incurable. Alpha-fetoprotein-producing gastric cancer has a poor prognosis and is prone to liver metastasis. We investigated the association between preoperative serum alpha-fetoprotein levels, liver metastasis, and expression of primitive enterocyte phenotype markers. We reviewed the medical records of 401 patients with gastric cancer who underwent curative surgical resection and immunohistochemically evaluated the primitive phenotype markers. The preoperative serum alpha-fetoprotein levels were elevated and normal in 8 and 393 patients, respectively. Liver metastasis was more frequent in patients with higher preoperative alpha-fetoprotein levels. The 5-year postoperative recurrence-free survival and overall survival rates were significantly worse in patients with higher preoperative serum alpha-fetoprotein levels. Although alpha-fetoprotein and Glypican3 and Spalt-like transcription factor 4 tended to be stained with high preoperative serum alpha-fetoprotein levels, these markers were also positive in some patients with normal alpha-fetoprotein levels. In summary, patients with gastric cancer and high preoperative serum alpha-fetoprotein levels have a poor prognosis and high incidence of liver metastasis. Alpha-fetoprotein can help detect liver metastasis relating to the primitive enterocyte phenotype.
| S-EPMC10866906 | biostudies-literature
Project description:Fanconi anaemia (FA) is an inherited bone marrow failure syndrome (IBMFS) with a high cancer predisposition rate. Traditional diagnoses are made before age 10 years due to bone marrow failure (BMF) and characteristic birth defects. Up to 10% of published cases were adults at diagnosis. We hypothesized that FA subgroups diagnosed in childhood are distinct from those diagnosed as adults. We classified patients by age at diagnosis of FA as FA-PED (<18 years) or FA-ADULT (≥18 years). The National Cancer Institute IBMFS cohort included 178 FA-PED and 26 FA-ADULT cases. We compared various features; the cumulative incidences of first adverse events (severe BMF leading to haematopoietic cell transplant or death, leukaemia, or solid tumours) were compared using competing-risk analyses. FA-ADULT lacked the 'typical' FA features (birth defects and early-onset BMF or leukaemia), were mainly female, had more patients with FANCA genotype, and had or developed more head and neck squamous-cell carcinoma (HNSCC) and/or gynaecological cancers compared with FA-PED, albeit at similar ages in both subgroups. FA-ADULT is a distinct subgroup that remained unrecognized during childhood. Centres for adult haematology-oncology should consider FA diagnosis in patients with early-onset HNSCC or gynaecological cancer with or without haematologic problems.
| S-EPMC11844804 | biostudies-literature
Project description:The Fanconi anaemia (FA) pathway repairs DNA damage caused by endogenous and chemotherapy-induced DNA crosslinks, and responds to replication stress1,2. Genetic inactivation of this pathway by mutation of genes encoding FA complementation group (FANC) proteins impairs development, prevents blood production and promotes cancer1,3. The key molecular step in the FA pathway is the monoubiquitination of a pseudosymmetric heterodimer of FANCD2-FANCI4,5 by the FA core complex-a megadalton multiprotein E3 ubiquitin ligase6,7. Monoubiquitinated FANCD2 then recruits additional protein factors to remove the DNA crosslink or to stabilize the stalled replication fork. A molecular structure of the FA core complex would explain how it acts to maintain genome stability. Here we reconstituted an active, recombinant FA core complex, and used cryo-electron microscopy and mass spectrometry to determine its structure. The FA core complex comprises two central dimers of the FANCB and FA-associated protein of 100 kDa (FAAP100) subunits, flanked by two copies of the RING finger subunit, FANCL. These two heterotrimers act as a scaffold to assemble the remaining five subunits, resulting in an extended asymmetric structure. Destabilization of the scaffold would disrupt the entire complex, resulting in a non-functional FA pathway. Thus, the structure provides a mechanistic basis for the low numbers of patients with mutations in FANCB, FANCL and FAAP100. Despite a lack of sequence homology, FANCB and FAAP100 adopt similar structures. The two FANCL subunits are in different conformations at opposite ends of the complex, suggesting that each FANCL has a distinct role. This structural and functional asymmetry of dimeric RING finger domains may be a general feature of E3 ligases. The cryo-electron microscopy structure of the FA core complex provides a foundation for a detailed understanding of its E3 ubiquitin ligase activity and DNA interstrand crosslink repair.
| S-EPMC6858856 | biostudies-literature
Project description:Germline mutations affecting telomere maintenance or DNA repair may, respectively, cause dyskeratosis congenita or Fanconi anaemia, two clinically related bone marrow failure syndromes. Mice expressing p53(Δ31), a mutant p53 lacking the C terminus, model dyskeratosis congenita. Accordingly, the increased p53 activity in p53(Δ31/Δ31) fibroblasts correlated with a decreased expression of 4 genes implicated in telomere syndromes. Here we show that these cells exhibit decreased mRNA levels for additional genes contributing to telomere metabolism, but also, surprisingly, for 12 genes mutated in Fanconi anaemia. Furthermore, p53(Δ31/Δ31) fibroblasts exhibit a reduced capacity to repair DNA interstrand crosslinks, a typical feature of Fanconi anaemia cells. Importantly, the p53-dependent downregulation of Fanc genes is largely conserved in human cells. Defective DNA repair is known to activate p53, but our results indicate that, conversely, an increased p53 activity may attenuate the Fanconi anaemia DNA repair pathway, defining a positive regulatory feedback loop.
| S-EPMC4821997 | biostudies-literature
Project description:Exosomal microRNAs have recently been studied as the potential diagnostic marker for various malignancies, including hepatocellular carcinoma (HCC). The aim of this study was to investigate serum exosomal microRNA profiles as HCC diagnostic marker. Transmission electron microscopy and Western blot were used to identify serum exosomes. Deep sequencing was performed to screen differentially expressed microRNAs between HCC (n = 5) and liver cirrhosis (LC, n = 5) groups. Three upregulated and two downregulated microRNAs were selected for qPCR analysis. The levels of selected microRNAs were normalized to Caenorhabditis elegans miR-39 microRNA mimics. Serum exosomal level of miR-122, miR-148a, and miR-1246 was further analyzed and significantly higher in HCC than LC and normal control (NC) groups (P < 0.001), but not different from chronic hepatitis group (P > 0.05). The receiver operating characteristic curve was used to evaluate the diagnostic performance of candidate microRNAs. Area under the curve (AUC) of miR-148a was 0.891 [95% confidence interval (CI), 0.809-0.947] in discriminating HCC from LC, remarkably higher than alpha-fetoprotein (AFP) (AUC: 0.712, 95% CI: 0.607-0.803). Binary logistic regression was adopted to establish the diagnostic model for discriminating HCC from LC. And the combination of miR-122, miR-148a, and AFP increased the AUC to 0.931 (95% CI, 0.857-0.973), which can also be applied for distinguishing early HCC from LC. miR-122 was the best for differentiating HCC from NC (AUC: 0.990, 95% CI, 0.945-1.000). These data suggest that serum exosomal microRNAs signature or their combination with traditional biomarker may be used as a suitable peripheral screening tool for HCC.
| S-EPMC5943469 | biostudies-literature
Project description:BackgroundSerum alpha-fetoprotein (AFP) is the approved serum marker for hepatocellular carcinoma (HCC) screening. However, not all HCC patients show high (≥ 20 ng/mL) serum AFP, and the molecular mechanisms of HCCs with normal (< 20 ng/mL) serum AFP remain to be elucidated. Therefore, we aimed to identify biological features of HCCs with normal serum AFP by investigating differential alternative splicing (AS) between HCCs with normal and high serum AFP.MethodsWe performed a genome-wide survey of AS events in 249 HCCs with normal (n = 131) and high (n = 118) serum AFP levels using RNA-sequencing data obtained from The Cancer Genome Atlas.ResultsIn group comparisons of RNA-seq profiles from HCCs with normal and high serum AFP levels, 161 differential AS events (125 genes; ΔPSI > 0.05, FDR < 0.05) were identified to be alternatively spliced between the two groups. Those genes were enriched in cell migration or proliferation terms such as "the cell migration and growth-cone collapse" and "regulation of insulin-like growth factor (IGF) transport and uptake by IGF binding proteins". Most of all, two AS genes (FN1 and FAM20A) directly interact with AFP; these relate to the regulation of IGF transport and post-translational protein phosphorylation. Interestingly, 42 genes and 27 genes were associated with gender and vascular invasion (VI), respectively, but only eighteen genes were significant in survival analysis. We especially highlight that FN1 exhibited increased differential expression of AS events (ΔPSI > 0.05), in which exons 25 and 33 were more frequently skipped in HCCs with normal (low) serum AFP compared to those with high serum AFP. Moreover, these events were gender and VI dependent.ConclusionWe found that AS may influence the regulation of transcriptional differences inherent in the occurrence of HCC maintaining normal rather than elevated serum AFP levels.
| S-EPMC7771076 | biostudies-literature