Copyright ©The Author(s) 2020.
World J Gastroenterol. Jul 14, 2020; 26(26): 3720-3736
Published online Jul 14, 2020. doi: 10.3748/wjg.v26.i26.3720
Table 1 Summary of studies on intra-tumoral heterogeneity in hepatocellular carcinoma using single-cell sequencing
NoTimePatients (n)Cells (n)MethodsFindingsRef.
Studies on cancer cells
12016125 TscTrio-seq (DNA, DNA methylation, mRNA)Two subpopulations were identified based on CNVs, DNA methylome, or mRNA.[12]
22018396 T + 15 NSingle-cell WGSHCCs can be of monoclonal or polyclonal origins. Models of late dissemination and early seeding have a role in HCC progression.[13]
320181118 CSCs + 860 unsortedmRNA (SMART-Seq +10X)Different CSC subsets contain distinct molecular signatures, and are associated with prognosis.[14]
420191139 TmRNA (C1)EPCAM+ cells had upregulated expression of multiple oncogenes and sustain CSC property.[16]
Studies on immune cells
5201765063 T cellsmRNA (Smart-Seq2)11 T cell subsets were identified based on their molecular and functional properties.[80]
6201916CD45+ cells (66187 + 11134)mRNA (10X + Smart-Seq2)40 immune cell subsets were identified, as well as their distinct roles in HCC development.[81]
Studies on both
72019set1: 13 set2: 6set1: 5115set2: 4831mRNA (10X)Tumors with higher transcriptomic diversity were associated with higher VEGFA expression, lower cytolytic activities, and worse outcome.[17]
82019419625mRNA (microwell-seq)The extent of heterogeneity in both tumor and immune cells varies among patients.[72]
92020238553mRNA (10X)Cancer cells from the same tumor were divided into different Hoshida subclasses and had different effects on immune infiltration.[64]
Table 2 Summary of studies on intra-tumoral heterogeneity in hepatocellular carcinoma using multiregional sampling
NoTimePatients (n)Samples(n)MethodsFindingsRef.
Studies on cancer cells
120011129 T + 11 NIHC and TP53/CTNNB1 sequencingHeterogeneity existed in small HCC, accompanied by increased proliferative activity.[68]
2201523120 TIHC and TP53/CTNNB1 sequencingIntratumor heterogeneity may contribute to treatment failure and drug resistance in many cases of HCC.[67]
320151286 TWES/Genotyping20 unique cell clones were defined by WES. The size distribution of the clones revealed a non-Darwinian evolution model.[69]
4201618 HCC + 3 ICC +NWESIM showed similarity to a primary nodule and indicated that it could be an early event in HCC.[60]
520161043 T + 10 NWGS/WESUbiquitous mutations ranged from 8% to over90%. Satellite nodules occurred late in HCC.[57]
620171152 T + 6 N + 11 BWES + DNA methylation29% of putative driver mutations were present in the branches. DNA methylation heterogeneity was largely driven by the cancer self.[61]
72017951 T + 9 NWGS/WESTumor physically closer tend to be genetically more similar. HCC arose from ancestral clones and genetic lineages diverged as tumor grew.[59]
820172349 TWGS + RNA-seqGenetic diagnosis is good for an effective choice of therapeutic strategy and IM/MC determination.[58]
920175931 N + 120 TTDSTrunk events in early stages (TERT, TP53, and CTNNB1 mutations) were ubiquitous across different regions.[63]
102017532 T + 5 N + cfDNAWES + TDSSingle region TDS identified 70% of the total mutations, while the cfDNA covered 47.2% of total.[116]
1120171055 TWES53.8% of oncogenic alterations varied among subclones. Targetable alterations were identified in subregions from 4 HCCs.[121]
122018515 T + 5 NProteomicsDiagnostic outcome may drastically differ if different sectors of tumor are analyzed.[73]
132019634 T + 5 NWES + RNA-seqLargest tumor contained higher proportion of ancestral clones. RNA expression pattern was associated with E-S grade[62]
142019536WES + RNA-seq + proteomics + metabolomics + CyTOFComprehensive intratumoral heterogeneity exists in all dimensions, and the novel immunoclassification of HCC facilitates prognostic prediction and may guide therapy.[72]
152019113356 (T + N)WGS/WES/TDS + DNA methylationIntratumoral heterogeneity revealed interactions between genomic and epigenomic features associated with tumor progression and recurrence.[65]
16201988230 TIHC and TERT promoter sequencingDistinct marker expression in different nodules. Limited heterogeneity in metastasis compared to primary sites.[83]
Studies on immune cells
172018124919 TMultiplex IHCVarying degrees of intratumor heterogeneity of the immune microenvironment were observed.[74]
1820191379 TIHC + RNA-seqA single-region sample might be reliable for the evaluation of tumor immune infiltration in approximately 60%-70% of patients with HCC.[117]
1920191547 TWES + RNA-seq + TCR-seq + IHC + immunopeptidomesGenetic structure, neoepitope landscape, T cell profile and immunoediting status collectively shape tumor evolution.[79]
2020201451 T + 20 NWES + RNA-seq + TCR-seq + SNP array + immunofluorescenceThe different components of the tumor ecosystem interact during cancer evolution, and promote heterogeneity in liver cancer.[64]