Table 1:
Summary of NGS resources and their key findings from liver cancer studies
| No. | Reference | Data URL | Sample type/total cases | Population | Viral status | Key findings |
|---|---|---|---|---|---|---|
| 1 | TCGA | https://dcc.icgc.org/projects/LIHC-US | 54 WGS (52 HCC, 1 ICC, 1 FC) | 39 White, 9 Asian, 3 African American, 3 Unknown | 7 HCV, 7 HBV, 40 NBNC | TCGA-LIHC-WGS |
| 2 | TCGA | https://portal.gdc.cancer.gov/projects/TCGA-LIHC | 376 WXS (366 HCC, 7 cHCC/ICC, 3 FC) + 371 RNA-seq (361 HCC, 7 cHCC/ICC, 3 FC) | 187/184 White, 160/158 Asian, 17 African American, 2 American Indian/Native, 10 Unknown | 49 HCV, 102 HBV, 8 HBV/HCV, 217 NBNC | TCGA-LIHC-WXS |
| 3 | Letouze et al. (2017) Nature Comm. https://doi.org/10.1038/s41467-017-01358-x | https://www.ebi.ac.uk/ega/studies/EGAS00001002408 | 44 WGS (35 HCC, 5 HCA, 4 FC) | 40 European, 4 African | 4 HCV, 5 HBV, 35 NBNC | 1. Analysis of more than 300 genomes highlighted 10 mutational signatures, including ubiquitous as well as sporadic signatures.2. Reconstruction of the temporal evolution in driver mutations and signatures revealed the clonal architecture in each tumor. |
| 4 | Ng et al. (2017) Sci. Transl. Med. https://doi.org/10.1126/scitranslmed.aan6446 | https://www.ebi.ac.uk/ega/studies/EGAS00001002301 | 98 WXS (HCC) | Asian (Taiwan) | 21 HCV, 56 HBV, 3 HBV/HCV, 10 NBNC, 8 N.D. | 1. Distinct mutational signatures were identified in the whole exomes of HCC patients with aristolochic acid exposure.2. The aristolochic acid signature also revealed known cancer driver genes, TP53 and CTNNB1, mutated 54 and 24 percent of the total HCC cases respectively. |
| 5 | Zhang et al., (2017) Gastroenterology. https://doi.org/10.1053/j.gastro.2017.03.024 | Unknown | 49 WGS + 13 WXS (HCC) | Asian (China) | 38 HBV, 9 NB, 2 N.D. | 1. Aflatoxin-associated HCCs were reported to frequently contain C>A transversions, sequence motif GCN, and strand bias.2. Frequent mutations identified in the adhesion G protein-coupled receptor B1 gene (ADGRB1) were found to be associated with increased capillary density of the tumor tissue. |
| 6 | Fujimoto et al. (2016) Nature Genetics. https://doi.org/10.1038/ng.3547 | https://dcc.icgc.org/projects/LIRI-JP https://www.ebi.ac.uk/ega/studies/EGAS00001000671 | 300 WGS (268 HCC, 24 ICC, 8 cHCC/ICC) + 254 RNA-seq | Asian (Japan) | 159 HCV, 82 HBV, 4 HBV/HCV, 55 NBNC | 1. Coding and noncoding regions (including NEAT1 and MALAT1) were identified to have significant mutations.2. Structural variation analysis revealed cancer-related genes (e.g., TERT and NCOR1) that led to altered expression. |
| 7 | Hirotsu et al. (2016) Hepatology Research https://doi.org/10.1111/hepr.12663 | http://trace.ddbj.nig.ac.jp/DRASearch/submission?acc=DRA003210 | 9 WXS (HCC) | Asian (Japan) | 1 HBV, 5 HCV, 3 NBNC | 1. Targeted deep sequencing analysis showed that TP53 (3/9 cases) and CTNNB1 (2/9 cases) were recurrent missense mutations in HCCs.2. Functional analysis of the β-catenin H36P mutant was observed to be resistant to protein degradation and to promote HCC cell proliferation. |
| 8 | Fujimoto et al. (2015) Nature Comm. https://doi.org/10.1038/ncomms7120 | https://dcc.icgc.org/projects/LIRI-JP | 90 WGS (60 HCC, 7 cHCC/ICC, 22 ICC, 1 CoCC) + 69 RNA-seq | Asian (Japan) | 60 HCC: 23 HBV, 29 HCV, 3 HBV/HCV, 5 NBNC | 1. cHCC/ICC and CoCC showing biliary epithelial differentiation (LCB) have recurrent mutations in the TERT promoter and chromatin regulators.2. Hepatitis-positive HCC and cHCC/CC had a larger frequency of TERT promoter mutations and a lower frequency of KRAS and IDH1/2 mutations than hepatitis-negative LCB. |
| 9 | Kang et al. (2015) Genomics https://doi.org/10.1016/j.ygeno.2014.11.005 | http://www.ebi.ac.uk/ena/data/view/ERP001196 http://gigadb.org/dataset/100034 | 9 WGS + RNA-seq (HCC) | Asian (Hong Kong) | HBV | 1. An improved bioinformatics pipeline detects RNA-editing events in HCC tumor and matched adjacent tissues.2. Varying editing degrees were significant in 13 cancer-related genes from 18 editing sites and one gene with editing in the CDS region between normal and tumor tissues. |
| 10 | Schulze et al. (2015) Nature Geneticshttps://doi.org/10.1038/ng.3252 | https://dcc.icgc.org/projects/LICA-FR https://www.ebi.ac.uk/ega/studies/EGAS00001000217 | 236 WXS (HCC) | European (193 France, 9 Spain, 41 Italy) | 57 HCV, 29 HBV, 4 HBV/HCV, 142 NBNC | 1. Mutational signatures were significantly associated with demographic, etiological, molecular features.2. Signature 23 that contained predominantly C>T mutations is consistent with the study by Totoki et al. (2011). |
| 11 | Nault et al. (2015) Nature Geneticshttps://doi.org/10.1038/ng.3389 | https://www.ebi.ac.uk/ega/studies/EGAS00001000217 | 193 WXS (HCC) | European (France) | 36 HCV, 22 HBV, 135 NBNC | 1. Clonal integration of the adeno-associated virus type 2 (AAV2) were identified in 11of 193 HCCs.2. AAV2 integrations occurred in known cancer driver genes including TERT, CCNA2, CCNE1, KMT2B, and TNFSF10. |
| 12 | Dong et al. (2015) PLoS Onehttps://doi.org/10.1371/journal.pone.0123175 | http://www.ncbi.nlm.nih.gov/bioproject/279878 | 55 RNA-seq (HCC) | Asian (China) | 49 HBV, 7 NBNC | 1. MLL4 was identified as the most frequent HBV integration site (8/44 cases).2. Gene expression levels of the 8 MLL4-integration-positive samples were significantly higher than wild-type tumor and adjacent tissues. |
| 13 | Totoki et al. (2014) Nature Geneticshttps://doi.org/10.1038/ng.3126 | http://www.ncbi.nlm.nih.gov/gap/?term=phs000509 https://www.ebi.ac.uk/ega/studies/EGAS00001000389 | 503 WXS (488 HCC, 2 cHCC/ICC, 13 ICC) | 414 Asian (Japan), 50 Caucasian, 14 US-Asian, 11 African American, 14 N.D. | 212 HCV, 117 HBV, 12 HBV/HCV, 150 NBNC, 9 N.D. | 1. Thirty candidate driver genes, including non-recurring mutated genes BRD7, MEN1, TSC2, SCRAP, and NCOR1 were identified.2. Distinct substitution signatures were detected between the various ancestries and gender but not associated with viral status. |
| 14 | Shirashi et al. (2014) PLoS Onehttps://doi.org/10.1371/journal.pone.0114263 | https://www.ebi.ac.uk/ega/datasets/EGAD00001001035 | 22 WGS + RNA-seq (HCC) | Asian (Japan) | HBV | 1. Comparison of genomic and transcriptomic reads identified 292 genomic mutation-related splicing aberrations.2. Twenty-three of 33 HBV-human fusions were reported to affect TERT, FN1, MLL4, as well as concentrated around the HBx genes. |
| 15 | Fernandez-Banet et al. (2014) Genomics https://doi.org/10.1016/j.ygeno.2014.01.003 | http://www.ebi.ac.uk/ena/data/view/ERP001196 http://gigadb.org/dataset/100034 | 88 WGS (HCC) | Asian (Hong Kong) | 81 HBV, 7 NBNC | 1. A total of 4,314 somatic genomic rearrangement (GR) events were detected and annotated at the single-nucleotide resolution.2. Five HCC tumors harbored chromothripsis on chromosomal arms 1q, 8q, and 5p; 13 genes, including CEBPB, MCL1, and AXIN1, were significantly affected by GR. |
| 16 | Jhunjhunwala et al. (2014) Genome Biology https://doi.org/10.1186/s13059-014-0436-9 | https://www.ebi.ac.uk/ega/studies/EGAS00001000824 | 12 WGS + RNA-seq (HCC) | Samples obtained from commercial sources | 11 HBV, 1 NBNC | 1. Recurrent mutations in TP53, AXIN1, and CTNNB1 were detected as well as a rare find in LAMA2 (6/42 cases) and IDH1 (2/42 cases).2. The activation of TERT was either due to viral integrations in its promoter or its translocation to another chromosomal region. |
| 17 | Ahn et al. (2014) Hepatology https://doi.org/10.1002/hep.27198 | Unknown | 231 WXS (HCC) | Asian (Korea) | 167 HBV, 22 HCV, 42 NBNC | 1. Nine significantly mutated genes and cellular pathways such as p53, Wnt, PIK3/Ras, cell cycle, and chromatin remodeling account for ∼80% of the mutations identified in the 231 tumors.2. Genetic aberrations in the cell cycle pathway genes (RB1, MYC, CCND1, RBL2) were associated with cancer-specific and recurrence-free survival. |
| 18 | Woo et al. (2014) PLoS One https://doi.org/10.1371/journal.pone.0115152 | Unknown | 12 WXS (HCC) | Asian (Korea) | HBV | 1. Tumor-specific genes such as CTNNB1, TTN, SETD2, and ALK have been identified.2. The T>A transversions were present significantly and exclusively in tumor-specific variants. |
| 19 | Ouyang et al. (2014) BMC Medical Genomics https://doi.org/10.1186/1755-8794-7-2 | https://trace.ddbj.nig.ac.jp/DRASearch/submission?acc=SRA076160 | 4 WGS (HCC) | Asian (Korea) | HBV | 1. Analysis of the mutational spectrum showed that C>T transition rates within the coding regions were the highest.2. Altered pathways in primary tumor were Wnt, JAK-STAT, cell cycle, and focal adhesion pathways, while tight junction, focal adhesion, and ErbB/MAPK pathways were affected in the metastases. |
| 20 | Kan et al. (2013) Genome Research https://doi.org/10.1101/gr.154492.113 | http://www.ebi.ac.uk/ena/data/view/ERP001196 http://gigadb.org/dataset/100034 | 88 WGS (HCC) | Asian (Hong Kong) | 81 HBV, 7 NBNC | 1. The study reveals recurrent mutations in TP53, CTNNB1 and AXIN1, two genes (JAK1, LRPB1) commonly mutated in other cancers as well as six genes previously not reported.2. Pathways affected include Wnt, cytokine-induced JAK/STAT, G1/S cell cycle, and apoptosis. |
| 21 | Toh et al. (2013) Carcinogenesis https://doi.org/10.1093/carcin/bgs406 | Unknown | 48 FLX-Seq (HCC) | Asian (Singapore) | 48 HBV | 1. Preferential integration of HBV into the TERT promoter (6/97 cases).2. The 3ʹ-end of the HBV X protein is the preferred HBV genomic region detected in the integration events. |
| 22 | Cleary et al. (2013) Hepatology https://doi.org/10.1002/hep.26540 | http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000627.v1.p1 | 87 WXS (HCC) | Samples obtained from Canada, North Carolina, and CHTN | 19 HCV, 38 HBV, 30 NBNC | 1. Thirteen significantly mutated genes identified include CTNNB1, TP53, CPA2, IGSF3, and KEAP1 as well as four significantly mutated gene families.2. Further validation of the MLL gene family revealed MLL4 (6/13 missense mutations) to be a potential driver gene of HCC. |
| 23 | Lin et al. (2013) Oncogene https://doi.org/10.1038/onc.2013.424 | https://trace.ddbj.nig.ac.jp/DRASearch/study?acc=SRP007560 | 55 RNA-seq (HCC) | Asian (Taiwan) | 20 HBV, 18 HCV, 17 NBNC | 1. Putative mRNA sequences filtered via Cufflinks de novo assembly identified, DUNQU1, a 101-amino-acid peptide encoded by 3 exons.2. Analysis of alternative splicing in transcripts revealed three cancer-related events in FGFR2, EXOC7, and ADAM15. |
| 24 | Fujimoto et al. (2012) Nature Genetics https://doi.org/10.1038/ng.2291 | https://dcc.icgc.org/projects/LINC-JP | 27 WGS (HCC) | Asian (Japan) | 11 HBV, 14 HCV, 2 NBNC | 1. TP53 and CTNNB1, as well as ATM, ARID1A, ERRF11, WWP1 mutations were detected in the tumors.2. Gene-set enrichment analysis identified several genes associated with chromatin regulation. |
| 25 | Sung et al. (2012) Nature Genetics https://doi.org/10.1038/ng.2295 | http://www.ebi.ac.uk/ena/data/view/ERP001196 http://gigadb.org/dataset/100034 | 88 WGS (HCC) | Asian (Hong Kong) | 81 HBV, 7 NBNC | 1. A total of 179 of the 399 HBV integration breakpoints were identified in known coding genes.2. HBV integrations led to increased gene expression of TERT, MLL4, and CCNE1. |
| 26 | Guichard et al. (2012) Nature Genetics https://doi.org/10.1038/ng.2256 | https://www.ebi.ac.uk/ega/studies/EGAS00001000217 | 24 WXS (HCC) | European (France) | 4 HCV, 1 HBV, 19 NBNC | 1. A total of 850 mutations corresponded to single-nucleotide variants, particularly C>T changes that occur more frequently in non-cirrhotic liver HCC tumors.2. Major pathways with frequently altered genes identified include Wnt and p53 pathways as well as four recurrent mutations (ARID1A, RPS6KA3, NFE2L2, and IRF2) previously not reported. |
| 27 | Jiang et al. (2012) Genome Research https://doi.org/10.1101/gr.133926.111 | http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000384.v1.p1 | 4 WGS + RNA-seq (HCC) | Samples obtained from commercial sources | 3 HBV, 1 NBNC | 1. RNA-seq expression analysis revealed the impact of HBV integrations on adjacent transcription activation of MLL4 and ANGPT1 in different patients.2. There is a strong bias of viral-fusion transcripts containing HBV genome sequences near its direct repeat 1 (DR1) region. |
| 28 | Huang et al. (2012) Nature Genetics https://doi.org/10.1038/ng.2391 | http://www.ncbi.nlm.nih.gov/bioproject/PRJNA167270 | 10 WXS (HCC) | Asian (China) | 8 HBV, 2 NBNC | 1. The comparison between matched samples of HBV-associated HCC individuals (primary tumor vs. portal vein tumor thromboses) reveals 65 mutations including TP53 and ARID1A.2. ARID1A mutations were also identified in four HCC cell lines with high metastatic potential. |
| 29 | Totoki et al. (2011) Nature Genetics https://doi.org/10.1038/ng.804 | https://dcc.icgc.org/projects/LINC-JP | 1 WGS (HCC) | Asian (Japan) | HCV | 1. The study identified somatic substitutions patterns predominantly from T>C and C>T transitions.2. Somatic alterations include well-known tumor suppressors TP53 and AXIN1 as well as five other genes found commonly mutated in other cancers. |
| 30 | Li et al. (2011) Nature Genetics https://doi.org/10.1038/ng.903 | Unknown | 139 WXS (HCC) | US (44 White, 15 Black, 9 Asian, 1 Hispanic, 1 Arabic, 8 Unknown), China (61 Asian) | 43 HCV, 50 HBV, 2 HBV/HCV, 44 NBNC | 1. Somatic mutations were found in five genes (CTNNB1, TP53, ARID2, DMXL1, and NLRP1).2. Six of nine of the samples containing ARID2 mutations also contained CTNNB1 mutations but none of them contained TP53 mutations. |
| Total | Total | |||||
| 582 WGS; 1211 WXS; 778 RNA-seq; 48 FLX-seq | 43.71% HBV; 21.13% HCV; 34.48% NBNC |