Molecular subtypes of intrahepatic cholangiocarcinoma

Trends in Molecular Medicine, Год журнала: 2025, Номер unknown

Опубликована: Фев. 1, 2025

Intrahepatic cholangiocarcinoma (iCCA) presents in two clinically distinct subtypes: large duct (LD-iCCA) and small (SD-iCCA). These subtypes exhibit significant molecular, genetic, histopathological differences that impact patient prognosis treatment responsiveness. This review advocates for a subtype-specific approach to iCCA research clinical management, including tailored therapeutic strategies consider genetic profiles tumor microenvironments. Current approaches hold promise, yet efficacy varies by subtype. Additionally, molecular diagnostics, DNA methylation-based classifiers transcriptomic sequencing, have shown potential refining subclassification, thereby guiding precision medicine efforts. article outlines existing trials, key trajectories, future directions developing more effective subtype-adapted therapies iCCA.

Язык: Английский

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Association of BRAF Variants With Disease Characteristics, Prognosis, and Targeted Therapy Response in Intrahepatic Cholangiocarcinoma

JAMA Network Open, Год журнала: 2023, Номер 6(3), С. e231476 - e231476

Опубликована: Март 3, 2023

Importance BRAF variants are associated with tumor progression; however, the prevalence of variant subtypes and their association disease characteristics, prognosis, targeted therapy response in patients intrahepatic cholangiocarcinoma (ICC) largely unknown. Objective To explore ICC. Design, Setting, Participants In this cohort study, 1175 who underwent curative resection for ICC from January 1, 2009, through December 31, 2017, were evaluated at a single hospital China. Whole-exome sequencing, Sanger sequencing performed to identify variants. The Kaplan-Meier method log-rank test used compare overall survival (OS) disease-free (DFS). Univariate multivariate analyses using Cox proportional hazards regression. Associations between tested 6 -variant, patient-derived organoid lines 3 patient donors those lines. Data analyzed June 2021, March 15, 2022. Interventions Hepatectomy Main Outcomes Measures OS DFS. Results Of ICC, mean (SD) age was 59.4 (10.4) years 701 (59.7%) men. A total 20 different somatic variance affecting 49 (4.2%) identified; V600E most frequent allele cohort, accounting 27% identified variants, followed by K601E (14%), D594G (12%), N581S (6%). Compared non-V600E more likely have large size (10 13 [77%] vs 12 36 [33%]; P = .007), multiple tumors (7 [54%] 8 [22%]; .04), vascular/bile duct invasion .04). Multivariate analysis revealed that but not or poor (hazard ratio [HR], 1.87; 95% CI, 1.05-3.33; .03) DFS (HR, 1.66; 1.03-2.97; There also broad differences among organoids sensitivity MEK inhibitors. Conclusions Relevance findings study suggest there Identifying classifying may be able help guide precise treatment

Язык: Английский

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Molecular Profile of Intrahepatic Cholangiocarcinoma

International Journal of Molecular Sciences, Год журнала: 2023, Номер 25(1), С. 461 - 461

Опубликована: Дек. 29, 2023

Intrahepatic cholangiocarcinoma (ICC) is a relatively uncommon but highly aggressive primary liver cancer that originates within the liver. The aim of this study to review molecular profile intrahepatic and its implications for prognostication decision-making. This comprehensive characterization ICC tumors sheds light on disease’s underlying biology offers foundation more personalized treatment strategies. narrative prognostic therapeutic role ICC. Knowing helps determine prognosis support certain target therapies. panel in select patients specific therapies, predict responses, monitor responses. Precision medicine can promote improvement reduce unnecessary toxicity might have significant management following years. main mutations are tumor protein p53 (TP53), Kirsten rat sarcoma virus (KRAS), isocitrate dehydrogenase 1 (IDH1), AT-rich interactive domain-containing 1A (ARID1A). rate varies significantly each population. Targeting TP53 KRAS challenging due natural characteristics these genes. Different stages clinical studies shown encouraging results with inhibitors mutated IDH1 therapy ARID1A downstream effectors. Fibroblast growth factor receptor 2 (FGFR2) fusions an important Immune checkpoint blockade be applied small percentage patients. Molecular profiling represents groundbreaking approach understanding managing complex cancer. As our comprehension ICC’s intricacies continues expand, so does potential offering precise effective treatments. integration into practice signifies dawn new era care, emphasizing ongoing battle against malignancy.

Язык: Английский

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Integrative analyses of bulk and single-cell transcriptomics reveals the infiltration and crosstalk of cancer-associated fibroblasts as a novel predictor for prognosis and microenvironment remodeling in intrahepatic cholangiocarcinoma

Journal of Translational Medicine, Год журнала: 2024, Номер 22(1)

Опубликована: Май 3, 2024

Abstract Background Intrahepatic cholangiocarcinoma (ICC) is a highly malignant neoplasm and characterized by desmoplastic matrix. The heterogeneity crosstalk of tumor microenvironment remain incompletely understood. Methods To address this gap, we performed Weighted Gene Co-expression Network Analysis (WGCNA) to identify construct cancer associated fibroblasts (CAFs) infiltration biomarker. We also depicted the intercellular communication network important receptor-ligand complexes using single-cell transcriptomics analysis Adjacent normal tissue. Results Through intersection TCGA DEGs WGCNA module genes, 784 differential genes related CAFs were obtained. After series regression analyses, score was generated integrating expressions EVA1A, APBA2, LRRTM4, GOLGA8M, BPIFB2, their corresponding coefficients. In TCGA-CHOL, GSE89748, 107,943 cohorts, high group showed unfavorable survival prognosis ( p < 0.001, = 0.0074, 0.028, respectively). Additionally, drugs have been predicted be more sensitive high-risk 0.05). Subsequent dimension reduction clustering, thirteen clusters identified atlas. Cell-cell interaction unveiled significant enhancement signal transduction in tissues, particularly from cells via diverse pathways. Moreover, SCENIC indicated that HOXA5, WT1, LHX2 are fibroblast specific motifs. Conclusions This study reveals key role - oncocytes remodeling immunosuppressive intrahepatic cholangiocarcinoma. Subsequently, it may trigger cascade activation downstream signaling pathways such as PI3K-AKT Notch tumor, thus initiating tumorigenesis. Targeted aimed at disrupting fibroblasts-tumor cell interaction, along with enrichment pathways, show potential mitigating facilitates progression.

Язык: Английский

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Proteogenomic characterization of cholangiocarcinoma

Hepatology, Год журнала: 2022, Номер 77(2), С. 411 - 429

Опубликована: Июнь 18, 2022

Background and Aims: Cholangiocarcinoma (CCA) is a highly heterogeneous cancer with limited understanding few effective therapeutic approaches. We aimed at providing proteogenomic CCA characterization to inform biological processes treatment vulnerabilities. Approach Results: Integrative genomic analysis functional validation uncovered perturbations downstream of driver events including DPCR1 , RBM47 mutations, SH3BGRL2 copy number alterations, FGFR2 fusions in CCA. Proteomic clustering identified three subtypes distinct clinical outcomes, molecular features, potential therapeutics. Phosphoproteomics characterized targetable kinases CCA, suggesting strategies for CDK MAPK inhibitors. Patients HBV infection showed increased antigen processing presentation (APC) T cell infiltration, conferring favorable prognosis compared those without infection. The extrahepatic recommended the feasible application vascular endothelial‐derived growth factor Multiomics profiling presented distinctive characteristics large bile duct small intrahepatic immune landscape further revealed diverse tumor microenvironments, C1 C5 might benefit from checkpoint therapy. TCN1 was as prognostic biomarker, promoting by enhancing vitamin B12 metabolism. Conclusions: 217 CCAs 197 paired normal adjacent tissues their targets. multiomics analyses other databases some validations have indicated regarding clinical, biological, approaches management

Язык: Английский

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Intrahepatic cholangiocarcinoma: Tumour heterogeneity and its clinical relevance

Clinical and Molecular Hepatology, Год журнала: 2022, Номер 28(3), С. 396 - 407

Опубликована: Янв. 16, 2022

Treatment of intrahepatic cholangiocarcinoma (iCCA) is currently at a significant turning point due to the identification isocitrate dehydrogenase (IDH) mutations and fibroblast growth factor receptor (FGFR) fusions that can be targeted with available therapies. Clinical trials these therapies have been promising, iCCA patients who may benefit from treatments identified by pathological examination prior molecular investigations. This because IDH FGFR are mainly seen in small duct type iCCA, subtype defined 5th World Health Organization classification, which recognized diagnostic process. Therefore, pathology plays an important role precision medicine for not only confirming diagnosis, but also identifying treatments. However, caution advised as shows tumour heterogeneity, making it difficult distinguish hepatocellular carcinoma (HCC), combined HCC-CCA. review focuses on pathological/molecular features both subtypes (large types), well their pitfalls, clinical relevance, future perspectives.

Язык: Английский

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ARID1Amutations in cancer development: mechanism and therapy

Carcinogenesis, Год журнала: 2023, Номер 44(3), С. 197 - 208

Опубликована: Март 1, 2023

Abstract AT-Rich Interaction Domain 1A (ARID1A) is an important SWItch/Sucrose Non-Fermentation (SWI/SNF) chromatin remodeling complex subunit, and its coding gene has a high mutation frequency in many cancers. Current studies have reported that ARID1A mutational status correlated to cancer development, including cell proliferation, invasiveness, metastasis, morphological alterations. acts as tumor suppressor, regulating transcription, participating DNA damage response, influencing immune microenvironment signaling pathways. The absence of can lead widespread dysregulation expression initiation, promotion, progression. For patients with mutations, effective individualized treatment improve the prognosis patients. In this review, we aim discuss mechanism mutations development explore significance discoveries for treatment.

Язык: Английский

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New Era of Immune-Based Therapy in Intrahepatic Cholangiocarcinoma

Cancers, Год журнала: 2023, Номер 15(15), С. 3993 - 3993

Опубликована: Авг. 6, 2023

Intrahepatic cholangiocarcinoma (CC) accounts for approximately 20% of all biliary tract cancer (BTC) cases and 10-15% primary liver cases. Many patients are diagnosed with unresectable BTC, and, even among resectable the 5-year survival rate is 20%. The BTC incidence high in Southeast East Asia has increased worldwide recent years. Since 2010, cytotoxic chemotherapy, particularly combination gemcitabine + cisplatin (ABC-02 trial), been first-line therapy BTC. In 2022, a multicenter, double-blind, randomized phase 3 trial (TOPAZ-1 trial) examined addition programmed death-ligand 1 immunotherapy (durvalumab) to treatment, resulting significantly improved without notable additional toxicity. As result this trial, three-drug become new standard therapy, leading advances management first time since 2010. molecular profiling continued drive development targeted therapies use when fail. Typically, second-line decisions based on identified genomic alterations tumor tissue. Mutations fibroblast growth factor receptor 1/2/3, isocitrate dehydrogenase 1/2, neurotrophic tyrosine kinase A/B/C relatively frequent intrahepatic CC, precision medicines available that can target associated pathways. review, we suggest strategies systemic pharmacotherapy focus presenting results safety outcomes clinical trials evaluating immune checkpoint inhibitor

Язык: Английский

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NIPBL::NACC1 Fusion Hepatic Carcinoma

The American Journal of Surgical Pathology, Год журнала: 2023, Номер 48(2), С. 183 - 193

Опубликована: Дек. 4, 2023

Several reports describing a rare primary liver tumor with histologic features reminiscent of follicular thyroid neoplasms have been published under variety descriptive terms including thyroid-like, solid tubulocystic, and cholangioblastic cholangiocarcinoma. Although these tumors are considered to represent variants, they lack classic cholangiocarcinoma unique characteristics, namely immunoreactivity for inhibin NIPBL::NACC1 fusions. The purpose this study is present clinicopathologic molecular data large series better understand their pathogenesis. We identified 11 hepatic features. Immunohistochemical NACC1 NIPBL fluorescence in situ hybridization assays were performed on all cases. Four cases had available material whole-genome sequencing (WGS) analysis. Most patients adult women (mean age: 42 y) who presented abdominal pain masses size: 14 cm). Ten no known disease. Of the follow-up information, 3/9 (33%) pursued aggressive behavior. All composed bland cuboidal cells solid/trabecular growth patterns various combinations, immunoreactive inhibin, showed albumin mRNA by hybridization, harbored fusion hybridization. WGS corroborated presence 4 tested cases, high mutational burden 2 over 30 structural variants per case 3 sequenced tumors. lacked mutations typical conventional intrahepatic In report, we describe largest inhibin–positive harboring first analysis propose name neoplasm NIPBL:NACC1 carcinoma.

Язык: Английский

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A cuproptosis-related gene expression signature predicting clinical prognosis and immune responses in intrahepatic cholangiocarcinoma detected by single-cell RNA sequence analysis

Cancer Cell International, Год журнала: 2024, Номер 24(1)

Опубликована: Март 2, 2024

Abstract Background Cholangiocarcinoma represents a malignant neoplasm originating from the hepatobiliary tree, with subset of tumors developing inside liver. Intrahepatic cholangiocarcinomas (ICC) commonly exhibit an asymptomatic presentation, rendering both diagnosis and treatment challenging. Cuproptosis, emerging regulated cell death pathway induced by copper ions, has garnered attention recently. As cancer cells show altered metabolism comparatively higher needs, cuproptosis may play role in development ICC. However, studies investigating this possibility are currently lacking. Methods Single-cell bulk RNA sequence data were analyzed, correlations established between expression cuproptosis-related molecules ICC patient survival. Genes predicting survival used to create CUPT score using Cox LASSO regression tumor mutation burden (TMB) analysis. The CIBERSORT software was employed characterize immune infiltration within tumors. Furthermore, prediction, biological function enrichment, drug sensitivity analyses conducted explore potential implications signature. effects silencing solute carrier family 39 member 4 gene (SLC39A4) siRNA investigated assays measuring proliferation, colony formation, migration. Key genes detected western blotting. Results developed divided patients into high low groups. Those had significantly better prognosis longer In contrast, scores associated worse clinical outcomes TMB. Comparisons two groups also indicated differences infiltrate present Finally, we able identify 95 drugs potentially affecting pathway. Some these might be effective vitro experiments revealed that suppressing SLC39A4 lines resulted reduced It led increase upregulation key cuproptosis, namely ferredoxin 1 (FDX1) dihydrolipoyl transacetylase (DLAT). These findings strongly suggest cuproptosis-associated molecule pivotal metastasis Conclusions Changes signature can predict considerable accuracy. This supports notion influences diversity complexity microenvironment, mutational landscape, behavior Understanding hold promise for innovative strategies management disease.

Язык: Английский

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