Identifying and understanding the molecular mechanisms of migraine via functional interpretation of genome-wide association study (GWAS) data DOI Creative Commons
Ammarah Ghaffar

Published: Jan. 1, 2022

Migraine is the most common brain disorder, affecting almost 14% of adult population, yet its molecular mechanisms and pathogenic tissue(s) remain unclear. In this thesis, I have developed a novel approach that uses genome-wide association study (GWAS) summary statistics expression quantitative trait loci (eQTL) data to impute genetically regulated tissue-specific gene prioritise disease-relevant tissues. subsequent studies, compared three transcriptome imputation models characterise significant migraine GWAS risk identified 14 were confirmed be true in recent larger GWAS.

Language: Английский

Cholangiocarcinoma — novel biological insights and therapeutic strategies DOI
Sumera I. Ilyas, Silvia Affò, Lipika Goyal

et al.

Nature Reviews Clinical Oncology, Journal Year: 2023, Volume and Issue: 20(7), P. 470 - 486

Published: May 15, 2023

Language: Английский

Citations

93
Clinical relevance of biomarkers in cholangiocarcinoma: critical revision and future directions DOI
Rocı́o I.R. Macı́as, Vincenzo Cardinale, Timothy J. Kendall

et al.

Gut, Journal Year: 2022, Volume and Issue: unknown, P. gutjnl - 327099

Published: May 17, 2022

Cholangiocarcinoma (CCA) is a malignant tumour arising from the biliary system. In Europe, this frequently presents as sporadic cancer in patients without defined risk factors and usually diagnosed at advanced stages with consequent poor prognosis. Therefore, identification of biomarkers represents an utmost need for CCA. Numerous studies proposed wide spectrum tissue molecular levels. With present paper, multidisciplinary group experts within European Network Study discusses clinical role provides selection based on their current relevance potential applications framework Recent advances are by dividing diagnosis, prognosis therapy response. Limitations also identified, together specific promising areas (ie, artificial intelligence, patient-derived organoids, targeted therapy) where research should be focused to develop future biomarkers.

Language: Английский

Citations

52
Discovery of novel DNA methylation biomarker panels for the diagnosis and differentiation between common adenocarcinomas and their liver metastases DOI Creative Commons
Tina Draškovič, Nina Hauptman

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Feb. 7, 2024

Abstract Differentiation between adenocarcinomas is sometimes challenging. The promising avenue for discovering new biomarkers lies in bioinformatics using DNA methylation analysis. Utilizing a 2853-sample identification dataset and 782-sample independent verification dataset, we have identified diagnostic that are hypermethylated cancer differentiate breast invasive carcinoma, cholangiocarcinoma, colorectal cancer, hepatocellular lung adenocarcinoma, pancreatic adenocarcinoma stomach adenocarcinoma. best panels type exhibit sensitivity of 77.8–95.9%, specificity 92.7–97.5% tumors, 91.5–97.7% tumors normal tissues accuracy 85.3–96.4%. We shown the results can be extended from primary cancers to their liver metastases, as diagnose metastases carcinoma with 83.3–100% 86.8–91.9%. Moreover, could detect hypermethylation selected regions cell-free patients metastases. At same time, these were unmethylated healthy donors, confirming applicability liquid biopsies.

Language: Английский

Citations

10
Mapping the landscape of biliary tract cancer in Europe: challenges and controversies DOI Creative Commons
Lorenza Rimassa, Shahid A. Khan, Bas Groot Koerkamp

et al.

The Lancet Regional Health - Europe, Journal Year: 2025, Volume and Issue: 50, P. 101171 - 101171

Published: Feb. 19, 2025

Biliary tract cancer (BTC) is becoming more common worldwide, with geographic differences in incidence and risk factors. In Europe, BTC may be associated primary sclerosing cholangitis, lithiasis, liver cirrhosis, but frequently observed as a sporadic disease. increasingly affects patients under 60 years, resulting significant social economic burden. Early diagnosis remains challenging due to vague symptoms 50% of BTC, lack specific biomarkers, late presentation poor prognosis. The identification at increased reliable biomarkers require collaborative efforts make faster progress. This Series paper highlights the disparities access diagnostic tools multidisciplinary care particularly economically disadvantaged regions, while identifying priority areas for improvement. Addressing these inequities requires harmonised guidelines, accelerated pathways curative treatments, improved awareness among healthcare professionals public. Multidisciplinary teams (MDTs) are crucial improving patient outcomes, yet inconsistencies exist their implementation not only between different countries, also centres within country. Collaboration standardisation treatment protocols across Europe essential effectively address management BTC.

Language: Английский

Citations

1
The Search for Risk, Diagnostic and Prognostic Biomarkers of Cholangiocarcinoma and their Biological and Clinicopathological Significance DOI
Rocı́o I.R. Macı́as, Hiroaki Kanzaki, Carmen Berasain

et al.

American Journal Of Pathology, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 1, 2024

Language: Английский

Citations

4
New molecular mechanisms in cholangiocarcinoma: signals triggering interleukin-6 production in tumor cells and KRAS co-opted epigenetic mediators driving metabolic reprogramming DOI Creative Commons
Leticia Colyn, Gloria Álvarez‐Sola, María U. Latasa

et al.

Journal of Experimental & Clinical Cancer Research, Journal Year: 2022, Volume and Issue: 41(1)

Published: May 26, 2022

Cholangiocarcinoma (CCA) is still a deadly tumour. Histological and molecular aspects of thioacetamide (TAA)-induced intrahepatic CCA (iCCA) in rats mimic those human iCCA. Carcinogenic changes therapeutic vulnerabilities may be captured by investigations bile, where we performed bile proteomic metabolomic analyses that help discovery yet unknown pathways relevant to iCCA.Cholangiocarcinogenesis was induced (TAA) mice (JnkΔhepa + CCl4 DEN model). We from control CCA-bearing rats. Differential expression validated rat CCAs. Mechanisms were addressed cells, including Huh28-KRASG12D cells. Cell signaling, growth, gene regulation [U-13C]-D-glucose-serine fluxomics performed. In vivo studies the clinically-relevant iCCA mouse model.Pathways related inflammation, oxidative stress glucose metabolism identified analysis. Oxidative high amounts oncogenesis-supporting amino acids serine glycine discovered studies. Most hits confirmed CCAs (TCGA). Activation interleukin-6 (IL6) epidermal growth factor receptor (EGFR) pathways, key genes cancer-related metabolic reprogramming, TAA-CCAs. TAA-CCAs, G9a, an epigenetic pro-tumorigenic writer, also increased. show EGFR signaling mutant KRASG12D can both activate IL6 production Furthermore, phosphoglycerate dehydrogenase (PHGDH), rate-limiting enzyme serine-glycine pathway, upregulated correlating with G9a expression. activity-dependent manner, promoted PHGDH expression, flow towards synthesis, increased cell viability. CAA cells more sensitive inhibition than controls. iCCA, pharmacological targeting reduced expression.In CCA, new mechanisms: or KRAS mutation drives tumour cells; Glucose reprogramming includes activation pathway; Mutant G9a-dependent manner; emerge as targets

Language: Английский

Citations

19
Role of genomics in liver transplantation for cholangiocarcinoma DOI
Nadine Soliman, Anaum Maqsood, Ashton A. Connor

et al.

Current Opinion in Organ Transplantation, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 7, 2025

Purpose of review The purpose this is to summarize the current knowledge cholangiocarcinoma molecular biology and suggest a framework for implementation next-generation sequencing in all stages liver transplantation. This timely as recent guidelines recommend increased use these technologies with promising results. Recent findings main themes covered here address germline somatic genetic alterations recently discovered cholangiocarcinoma, particularly those associated prognosis treatment responses, nascent efforts translate into contemporary practice peri-liver transplantation period. Summary Early profiling care demonstrate growing number potentially actionable alterations. Still lacking consensus on what biomarkers adopt, at scale cost, how integrate them most effectively ambition increasing patients eligible improving their long-term outcomes.

Language: Английский

Citations

0
Mutational Analysis of Bile Cell‐Free DNA in Primary Sclerosing Cholangitis: A Pilot Study DOI Creative Commons
María Arechederra, Emil Bik, Carla Rojo

et al.

Liver International, Journal Year: 2025, Volume and Issue: 45(4)

Published: March 3, 2025

ABSTRACT Background Primary sclerosing cholangitis (PSC) is a chronic liver disease characterised by inflammation and fibrosis of the bile ducts, conferring an increased risk cholangiocarcinoma (CCA). However, detecting CCA early in PSC patients remains challenging due to limited sensitivity conventional diagnostic methods, including imaging or duct brush cytology during endoscopic retrograde cholangiopancreatography (ERCP). This study aims evaluate potential cell‐free DNA (cfDNA) mutational analysis, termed Bilemut assay, as tool for detection patients. Methods Sixty‐three undergoing ERCP biliary strictures were prospectively recruited. Bile samples collected, cfDNA was extracted analysed using Oncomine Pan‐Cancer Cell‐Free assay. Twenty healthy donors included comparison. Samples with mutant allele frequency (MAF) ≥ 0.1% considered positive. Correlations between status clinical characteristics assessed. Results analysis successful all samples. Mutations predominantly KRAS , GNAS TP53 detected 36.5% (23/63) patients, compared 10% (2/20) ( p = 0.0269). The Bilemut‐positive ‐negative comparable, though there trend towards lower prevalence inflammatory bowel group. Among diagnosed follow‐up, 75% Bilemut‐positive, suggesting association malignancy risk. Conclusions Mutational obtained from collected feasible. Implementing assay may help identify needing closer surveillance further studies.

Language: Английский

Citations

0
Integrating eQTL and GWAS data characterises established and identifies novel migraine risk loci DOI Creative Commons
Ammarah Ghaffar, Dale R. Nyholt

Human Genetics, Journal Year: 2023, Volume and Issue: 142(8), P. 1113 - 1137

Published: May 28, 2023

Migraine-a painful, throbbing headache disorder-is the most common complex brain disorder, yet its molecular mechanisms remain unclear. Genome-wide association studies (GWAS) have proven successful in identifying migraine risk loci; however, much work remains to identify causal variants and genes. In this paper, we compared three transcriptome-wide study (TWAS) imputation models-MASHR, elastic net, SMultiXcan-to characterise established genome-wide significant (GWS) GWAS loci, putative novel gene loci. We standard TWAS approach of analysing 49 GTEx tissues with Bonferroni correction for testing all genes present across (Bonferroni), five estimated be relevant migraine, that took into account correlation between eQTLs within each tissue (Bonferroni-matSpD). Elastic net models performed using Bonferroni-matSpD characterised highest number loci (n = 20) GWS having colocalisation (PP4 > 0.5) an eQTL. SMultiXcan identified 28) differential expression at 20 non-GWS Nine these were later found linkage disequilibrium true a recent, more powerful GWAS. Across approaches, total 62 32 independent genomic Of 21 Our results provide important guidance on selection, use, utility imputation-based approaches

Language: Английский

Citations

7
Cholangiocarcinoma: Molecular Abnormalities and Cells of Origin DOI Creative Commons
Ugo Testa, Elvira Pelosi, Germana Castelli

et al.

Technology in Cancer Research & Treatment, Journal Year: 2023, Volume and Issue: 22

Published: Jan. 1, 2023

Cholangiocarcinomas (CCAs) are a group of heterogeneous epithelial malignancies that can originate at the level any location biliary tree. These tumors relatively rare but associated with high rate mortality. CCAs morphologically and molecularly for their be distinguished as intracellular extracellular, subdivided into perihilar distal. Recent epidemiological, molecular, cellular studies have supported consistent heterogeneity observed may result from convergence various key elements mainly represented by risk factors, molecular abnormalities genetic epigenetic levels different potential cells origin. consistently contributed to better defining pathogenesis identify in some instances new therapeutic targets. Although progress were still limited, these observations suggest understanding mechanisms underlying CCA future will help develop more efficacious treatment strategies.

Language: Английский

Citations

6