Unveil Intrahepatic Cholangiocarcinoma Heterogeneity through the Lens of Omics and Multi-Omics Approaches
Abstract
:Simple Summary
Abstract
1. Introduction
2. Omics Cancer Era: From Single- to Multi-Omics Approaches
2.1. Single-Based Omics
2.2. Multi-Omics Approaches
3. Sequencing-Based Omics in iCCA
3.1. Genomics
3.2. Epigenomics
3.3. Transcriptomics
3.4. Epitranscriptomics
4. A Landscape Still Undiscovered: Proteomics and Metabolomics of iCCA
4.1. Proteomics
4.2. Metabolomics
5. Multi-Omics Approaches in iCCA: A New Model of Knowledge
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Single-Omics | Sample Type | Methods | Results | Refs. |
---|---|---|---|---|
Genomics | Ex vivo | RNA-seq; FISH; WES; Gene-array | Identification of 13 novel inter- and intrachromosomal fusion events; Top ranked fusion event: fusion of FGFR2 and PPHLN1 | [89] |
Ex vivo | NGS | 5547 genomic alterations in 335 genes: 3424 short variants, 1676 copy number variations | [43] | |
Ex vivo | WES | Detection of fusion transcripts FGFR2-AHCYL1, FGFR2- BICC1, AHCYL1-FGFR2, and BICC1-FGFR2 | [90] | |
Ex vivo | NGS | Most commonly mutated genes: KRAS (28.1%), TP53 (18.3%), ARID1A (11.8%), IDH1/IDH2 (9.2%), PBRM1 (9.2%), BAP1 (7.2%), and PIK3CA (7.2%) | [91] | |
Ex vivo | NGS | 1259 somatic mutations in 1128 genes | [92] | |
Ex vivo | Gene-array | 775 genetic alterations and 38 structural alterations | [42] | |
Ex vivo | NGS, WES, and WGS | Most recurrently mutated genes: TP53, KRAS, IDH1/2, ARID1A, BAP1, PBRM1, FGFR2 fusion, CDKN2A, SMAD4, PIK3CA, EPHA2 (mutation frequency > 5%) | [93] | |
Ex vivo | NGS | Most commonly mutated genes: TP53, ARID1A, KRAS, CDKN2A, SMAD4, and PBRM1 | [94] | |
Ex vivo | SNP-array | Copy number gain: chromosome 1q (32%) and 7p (25%); Copy number loss: 6q (52%), 9q (45%), 9p (42%), 3p (41%), 13q (38%), 14q (36%), 8p (30%), 21q (20%), 17p (21%), 4q (18%), 1p (16%), 18q (15%), and 11p (13%) | [95] | |
Ex vivo | Exome-array | Exclusively deleted cytobands: 1p36.33–1p35.1, 3p26.3–3p14.25, and 14q24.1–14q32.33; Exclusively amplified cytobands: 1p11.2–1p41.1, 1q21.1–1q44, 2q23.1–2q35, 7p22.3–7p11.1, 7q11.1–7q36.3, and 8q23.2–8q24.3 | [96] | |
Epigenomics | Ex vivo | Methylation-array | Methylation data used to classify tumors; general hypermethylation in iCCA samples | [97] |
Ex vivo | Methylation-array | cg15026696 hypomethylation and cg06972969 hypermethylation | [98] | |
In vitro | ChIP-sequencing | Reduced levels of H3K4me1, H3K4me3, and H3K27ac in tumor cells compared to normal cells | [99] | |
Ex vivo | Methylation-array | 2048 most variable CpG sites used to classify tumors | [100] | |
Ex vivo | WGBS | Identification of prognostically methylated regions (PMRs) as biomarkers | [101] | |
Ex vivo | WGBS | DNA methylation data used to classify tumors | [102] | |
Transcriptomics | Ex vivo | Transcriptome-array | Gene expression profiles used to classify iCCA tumors | [103] |
Ex vivo | RNA-sequencing | Gene expression profiles used to classify iCCA tumors | [104] | |
Ex vivo | RNA-sequencing and Transcriptome-array | C19orf33, S100P, CEACAM6, KRT17, GPRC5A, MSLN, SERPINB5, TCN1, OLFM4, VTN, ADH1C, ALDOB, FABP1, ADH1B, UGT2B7, APOC4, AQP9, CDO1, GSTA2 as biomarkers of specific iCCA subgroups | [105] | |
Ex vivo | mRNA and microRNA-array | 2327 DE mRNAs (1113 up- and 1214 downregulated) and 70 DE miRNAs (65 up- and 5 downregulated) in iCCA vs. paired non-cancerous liver tissue samples | [106] | |
Ex vivo | RNA-seq | 230 DE lncRNAs (97 up- and 133 downregulated) and 2220 DE mRNAs (640 down- and 1580 upregulated) in iCCA vs. paired unaffected tissues; top downregulated genes: RP11-328K4.1, LINC01093, LINC00844, RP11-372E1.4, ITIH4-AS1; top upregulated genes: RP11-532F12.5, AC016735.1, RP11-284F21.7, LINC01123, AC013275.2 | [107] | |
Ex vivo | GEP; Transcriptome-array; NGS | 315 DE genes (65 down- and 250 upregulated) in recurrent compared with primary tumors | [108] | |
Ex vivo | miRNA-seq | miR-10b, miR-22, and miR-551b significantly associated with OS in iCCA patients; Overexpression of miR-551b decreased HuCCT-1 proliferation and promoted apoptosis | [109] | |
Ex vivo | RNA-sequencing | 1643 DE transcripts (1098 up- and 545 downregulated) | [110] | |
Ex vivo | microRNA-array, and RNA-sequencing | Pathway enrichment analysis performed on DE lncRNAs and mRNAs revealed their involvement in the Hippo pathway | [111] | |
Ex vivo | Transcriptome-array | Gene expression profiles used to classify iCCA tumors; identification of ICCA-specific DE genes (395 up- and 5889 downregulated); Upregulated: ARHGAP21; Downregulated: SCP2, UBIAD1, TJP2, RAP1A, HDAC9, FKBP2, MRPL2, and MRPL27 | [112] | |
Ex vivo | Transcriptome-array | Classification of iCCA tumors according to 794 DE transcripts (486 up- and 308 downregulated) specific for cholangiolocellular differentiation (CD); specific of CD-tumors: CRP; specific of non-CD-tumors: S100P, TFF1, AGR2, CLDN18, KRT17, and CTSE | [113] | |
Ex vivo | single-cell RNA-seq | Gene expression profiles used to classify cells | [114] | |
Ex vivo | RNA-sequencing | Gene expression profiles used to classify iCCA tumors | [115] | |
Ex vivo | Transcriptome-array | 2611 (1142 up- and 1469 downregulated) | [116] | |
Ex vivo | STS; WES; WGS; NGS; Methylation-array | Gene expression profiles used to classify iCCA tumors; 52 genes showed differential expression between Cluster1A and Cluster2 | [93] | |
Ex vivo | circRNA-sequencing | 4 circRNAs upregulated in metastatic vs. non-metastatic tumors (circZNF215, circBNIP3L, circCD109, and circPLOD2) | [117] | |
Ex vivo | Transcriptome-array | 173 DE circRNAs (69 up- and 104 downregulated), 58 DE miRNAs (30 up- and 28 downregulated), and 4437 DE mRNAs (2234 up- and 2203 downregulated) | [118] | |
Ex vivo | RNA-sequencing | 262 dysregulated miRNAs (128 up- and 134 downregulated); top upregulated miRNAs: miR-21, miR-34c, miR-200b, and miR-221 | [119] | |
Epitransctriptomics | Ex vivo | Methylated RNA immunoprecipitation sequencing | METTL14 p.R298H mutation affected m6A modifications on the target MACF1 | [120] |
Proteomics | Ex vivo | Nano-LC-MALDI-TOF/TOF | Overexpression of COL3A1 and low levels of reticular and elastic fibers; Basement membrane dismantling; Reduced angiogenesis; COL3A1 promotes iCCA cell migration | [121] |
Ex vivo | AMT Tag | Altered protein network involved in cytoskeleton organization and cell motility (increase in vimentin, cofilin-1, profilin-1, and transgelin-2, S100A11, reduction in annexins) | [122] | |
Ex vivo | TMT | Decreased cell–cell junction level in HBV-iCCA; Inverse relationship between cell–cell junction level and EMT program: reduced abundance of epithelial cells is correlated with low expression levels of E-CAD in HBV-iCCA | [123] | |
Ex vivo | DIA-MS | Enrichment of proteins related to lipid metabolism (i.e., AMACR, SREBP, FASN) in HCC tissues; High levels of proteins involved in ECM-related pathways (S100A6, laminin interactions, assembly of collagen fibrils, PTK2 signaling) in iCCA tissues; S100A6 potential diagnosis biomarker to discriminate iCCA from HCC. | [124] | |
Ex vivo | LC-MS/MS | Overexpression of angio-inhibitory proteins in iCCA-ECF; Upregulation of THBS1, THBS2, and PEDF inhibits angiogenesis on behalf of lymphangiogenesis promoting the trans-differentiation of vascular endothelial cells toward a lymphatic phenotype | [40] | |
Metabolomics | Ex vivo | iTRAQ labeling and LC-MS/MS | Downregulation of enzymes (TPI1, GAPDH, and PGK1) involved in glycolysis and gluconeogenesis pathways in LDT compared to SDT | [125] |
Ex vivo | MS | High mitochondrial activity, with an enrichment of glutamine and glucose uptake; upregulation of glucose transporter SLC2A3; positive correlation between SLC2A3 and EMT markers (i.e., N-CAD) | [126] | |
Ex vivo | MALDI-MS and MALDI-MS/MS | Upregulation of enzymes (i.e., CAT, PRDX2/6, and SODM) involved in redox homeostasis causing accumulation of free radicals in iCCA patients | [127] | |
Ex vivo | GC–MS | Overactivation of linoleic acid metabolism pathway in IBDS rather than in iCCA tissues; 9,12-octadecadienoic acid potential biomarker for long-term monitoring, and treatment of IBDS to prevent the risk of iCCA development | [128] | |
Ex vivo | UPLC-MS/MS | 4 urinary metabolites (CR, NANA, CS, and 561+) are upregulated in iCCA compared to HCC patients; Potential model of iCCA diagnosis based on the combination of the 4 urinary metabolites and CA19-9 | [129] |
Multi-Omics | Sample Type | No of iCCA Patients | Methods | Results | Refs. |
---|---|---|---|---|---|
Genomics + Epigenomics | Ex vivo and In vitro | 71 | WGS; MiGS | 4 clusters based on strict correlation between phenotype and etiological agents | [189] |
Genomics + Epigenomics + Transcriptomics | Ex vivo | 38 | NGS; WES; RNA-seq; miRNA-seq; SNP-array | 4 clusters according to genomics, epigenomics, and transcriptomics profile | [88] |
Genomics + Epigenomics | Ex vivo | 52 | WGS; WES | 4 subgroups (IDH, L, M, H) based on genetic and epigenetic features | [97] |
Genomics + Epigenomics integrated with WES, RNA-seq, and proteome datasets | Ex vivo and Invitro | 331 | WGBS; TMA; WES | 4 clusters (S1–S4) according to hyper-differentially methylated regions (DMRs) | [102] |
Genomics + Epigenomics + Transcriptomics | Ex vivo | 149 | bs-DNA; Methylation-array; RNA-seq | 2 iCCA classes (inflammation and proliferation) based on genomic and mutational profiles | [95] |
Epigenomics + Transcriptomics | Ex vivo | 116 | Methylation-Array; Transcriptome-Array | 4 iCCA subtypes are identified according to different escape mechanisms in TME (immune desert, immunogenic, myeloid, and mesenchymal | [103] |
Proteomics + Genomics + Epigenomics + Transcriptomics | Ex vivo | 110 | TMT; NGS; WES; Single-cell RNA-seq | 3 molecular iCCA subtypes (chromatin remodeling, metabolism, and chronic inflammation) correlated to OS | [223] |
Proteomics + Epigenomics | Ex vivo | 962 | mIHC; WES | 4 iCCA classes based on the spatial distribution, abundance, and functional orientation of TLSs (immune excluded, altered, active) | [224] |
Genomics + Transcriptomics + Proteomics | Ex vivo | 255 | WES; Single-cell RNA-seq; MS; mIHC + TMA; | 3 iCCA subgroups (IG1-3) established by immune landscape | [225] |
Genomics + Transcriptomics + Proteomics | Ex vivo | 45 | WGS, RNA-seq; mIHC | 3 iCCA subgroups (sparsely, heterogeneously, and highly infiltrated) correlated to immunogenomics profiles | [226] |
Genomics + Transcriptomics + Proteomics | Ex vivo | 192 | mIHC; Molecular Signatures Database ((MSigDB) | 3 iCCA spatial immunophenotypes (inflamed, excluded, and ignored) based on immune infiltration | [227] |
Genomics + Transcriptomics | Ex vivo | 961 | NMF; Transcriptomic tools (i.e., EnrichR); Molecular Signatures Database (MSigDB) | 5 iCCA classes (STIM classification) related to the stroma, tumor, and immune microenvironment | [228] |
Genomics + Epigenomics + Transcriptomics + Proteomics | Ex vivo | 16 | WES; RNA-seq; Methylation-Array; mIHC; scRNA-seq; Single-cell RNA-seq | 2 iCCA groups according to ITH index (-high and -low) | [229] |
Genomics + Transcriptomics + Proteomics | Ex vivo | 262 | RNA-seq; TCR-seq; FISH; Fusion-derived peptides; peptide-array | 4 iCCA subgroups (S1–S4) with specific features in terms of genetic alterations, microenvironment dysregulation, tumor microbiota composition, and OS | [230] |
Genomics + Transcriptomics + Proteomics | Ex vivo | 102 | WES; RNA-seq; LC-MS/MS | 3 iCCA clinical subtypes (stem-like, poorly immunogenic, and metabolism) | [231] |
Genomics + Transcriptomics + Proteomics | Ex vivo | 116 | WES; RNA-seq; MS | 3 iCCA subgroups (S1–S3) according to metabolomics profile | [232] |
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Porreca, V.; Barbagallo, C.; Corbella, E.; Peres, M.; Stella, M.; Mignogna, G.; Maras, B.; Ragusa, M.; Mancone, C. Unveil Intrahepatic Cholangiocarcinoma Heterogeneity through the Lens of Omics and Multi-Omics Approaches. Cancers 2024, 16, 2889. https://doi.org/10.3390/cancers16162889
Porreca V, Barbagallo C, Corbella E, Peres M, Stella M, Mignogna G, Maras B, Ragusa M, Mancone C. Unveil Intrahepatic Cholangiocarcinoma Heterogeneity through the Lens of Omics and Multi-Omics Approaches. Cancers. 2024; 16(16):2889. https://doi.org/10.3390/cancers16162889
Chicago/Turabian StylePorreca, Veronica, Cristina Barbagallo, Eleonora Corbella, Marco Peres, Michele Stella, Giuseppina Mignogna, Bruno Maras, Marco Ragusa, and Carmine Mancone. 2024. "Unveil Intrahepatic Cholangiocarcinoma Heterogeneity through the Lens of Omics and Multi-Omics Approaches" Cancers 16, no. 16: 2889. https://doi.org/10.3390/cancers16162889
APA StylePorreca, V., Barbagallo, C., Corbella, E., Peres, M., Stella, M., Mignogna, G., Maras, B., Ragusa, M., & Mancone, C. (2024). Unveil Intrahepatic Cholangiocarcinoma Heterogeneity through the Lens of Omics and Multi-Omics Approaches. Cancers, 16(16), 2889. https://doi.org/10.3390/cancers16162889