Research ArticleArticles
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Genetic Analyses of Primary Liver Cancer Cell Lines: Correspondence With Morphological Features of Original Tumors

JUN AKIBA, SACHIKO OGASAWARA and HIROHISA YANO
Cancer Genomics & Proteomics May 2024, 21 (3) 260-271; DOI: https://doi.org/10.21873/cgp.20445

Abstract

Background/Aim: Advancements in genetic analysis technologies have led to establishment of molecular classifications systems for primary liver cancers. The correlation between pathological morphology and genetic mutations in hepatocellular carcinoma (HCC) is becoming increasingly evident. To construct appropriate experimental models, it is crucial to select cell lines based on their morphology and genetic mutations. In this study, we conducted comprehensive genetic analyses of primary liver cancer cell lines and examined their correlations with morphology. Materials and Methods: Thirteen primary liver cancer cell lines established in our Department were investigated. Eleven cell lines were HCC cell lines, whereas 2 were combined hepatocellular-cholangiocarcinoma (CHC) cell line characteristics. Whole exome sequencing and fusion gene analyses were conducted using a next generation sequencing platform. We also examined correlations between cell mutations and morphological findings and conducted experiments to clarify the association between morphological findings and genetic alterations. Results: Mutations in TP53, HMCN1, PCLO, HYDIN, APOB, and EYS were found in 11, 5, 4, 4, 3, and 3 cell lines, respectively. CTNNB1 mutation was not identified in any cell line. The original tumor of four cell lines (KYN-1, KYN-2, KYN-3, and HAK-6) showed morphologically macrotrabecular massive patterns and these cell lines harbor TP53 mutations. Two cell lines (KYN-2 and KMCH-2) showed an extremely high tumor mutation burden. These two cell lines possess ultra-mutations associated with DNA repair and/or DNA polymerase. Conclusion: The study identified correlations between morphological findings and genetic mutations in several HCC cell lines. Cell lines with unique genetic mutations were found. This information will be a valuable tool for the selection of suitable experimental models in HCC research.

Key Words:

Primary liver cancer is the sixth most common cancer and was the third leading cause of cancer-related death worldwide in 2020 (1). Primary liver cancer includes hepatocellular carcinoma (HCC) (accounting for 75%-85% of cases), followed by intrahepatic cholangiocarcinoma (iCCA) (10%-15%) and combined hepatocellular-cholangiocarcinoma (cHCC-CCA) (2-5%), as well as other rare types (1, 2).

Multimolecular targeted agents (MTAs) and/or immune checkpoint inhibitors (ICIs) are used worldwide in advanced HCC (3, 4). Some predictable factors have been advocated. Non-viral-related HCC, most of which is strongly associated with fatty liver disease, is one of the statuses to predict low efficacy to ICIs (3). Another possible factor is CTNNB1 mutation. CTNNB1-mutated HCC is resistant to ICIs therapy (5). Rendering mutant tumors immunologically cold, oncogenic WNT/b-catenin signaling leads to T-lymphocyte exclusion and insensitivity to combination ICIs, such as anti– programmed death-ligand-1(PD-L1) and anti–cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) monoclonal antibody therapy, in vivo (6, 7).

With technological advancements in genetic analysis, classification systems based on genetic mutations have been established for various carcinomas, including primary liver cancers. Although several classifications have been advocated (8-10). HCC can simply be divided into proliferating class and non-proliferating class (11, 12). The former is closely associated with TP53 mutations, the latter with CTNNB1 mutation. Recently, classifications considering a tumor immune microenvironment have been advocated (13-15).

To develop appropriate experimental systems, selecting cell lines based on genetic mutations is crucial. Most cell lines widely used in various experiments lack detailed clinical information. Some morphologic patterns are known to be associated with specific gene mutation (10). Therefore, cell lines with detailed clinical information and morphological patterns are quite unique. In this study, we aimed to conduct comprehensive genetic analyses in primary liver cancer cell lines, which were established and maintained in our Department. Moreover, we conducted morphological analysis of the original tumor and some experiments which clarified an association of the genetic alterations.

Materials and Methods

Cell lines establishment. We used 13 primary liver cancer cell lines that were established in the Department of Pathology, Kurume University School of Medicine (16-23). The establishment of all cell lines followed the procedures outlined in our previous reports (16-23). Of these, 13 primary liver cancer cell lines, 11 were HCC cell lines, whereas two were cHCC-CCA cell lines (18, 21). Two HCC cell lines (HAK-1A and HAK-1B) were established from different histological grades of the same nodule (20). This study was conducted in accordance with the Declaration of Helsinki and was approved by the ethics committee of Kurume University (approval #451).

Morphological assessment of original tumor. Detailed information of original tumor is provided in Table I. All liver specimens were obtained through surgery or autopsy. Liver specimens were fixed in 10% formalin and embedded in paraffin. We cut 4-μm consecutive sections and stained them with hematoxylin and eosin. Morphological assessment of the original tumor was conducted following the latest WHO classification (24) as well as the general rules for clinical and pathological study of primary liver cancer, edited by the liver cancer study group of Japan (25).

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Table I.

The clinicopathological findings of original tumor of 13 liver cancer cell lines.

Next-generation sequencing. Whole exome sequencing libraries were prepared using the SureSelectXT Human All Exon V6 kit (Agilent Technologies, Inc., Santa Clara, CA, USA), according to the manufacturer’s standard protocol. Libraries were sequenced on the Illumina Hiseq sequencer (Illumina, Inc., San Diego, CA, USA). The sequencing reads were mapped to the human GRCh37, and we performed the variant calling by using samtools mpileup v1.3 (26). After variant calling, we filtered out low-quality variants and common SNPs to identify somatic variants. We excluded variants that met any of the following criteria: MAF (minor allele frequency) >0.14% in the 1000 genome database, MAF >5% in each population of the 1000 genome database, SNPs found in 2 or more people in the human genetic variation database, and the variants found in control DNA. Then we calculated tumor mutation burden (TMB) by dividing the total number of somatic variants by the target size of the SureSelect capture (Mutation/Mb). To compare the mutation status of cell lines, data from a previous report on the mutation status of the clinical HCC sample was used (27).

KMCH-2 tissue preparation and immunohistochemical staining for mismatch repair protein. Cultured KMCH-2 cells (5.0×106 cells/mouse) were subcutaneously injected into the backs of 4-week-old female BALB/c athymic nude mice (Clea Japan, Inc, Osaka, Japan) following our previous study (28). The mice were sacrificed after 5 weeks, and the tumors were removed. Specimens were fixed in 10% formalin and embedded in paraffin blocks. Unstained 4-μm sections were cut from the blocks and stained with hematoxylin-eosin staining for light microscopic observation. Immunohistochemistry for formalin-fixed paraffin-embedded sections was performed. Unstained sections were immunostained with antibodies against human mismatch repair (MMR) proteins following the method described previously (29). Briefly, the expression of MMR proteins was assessed using a four-antibody immunohistochemical assay targeting MutL homolog 1 (MLH1 clone; ES05), MutS homolog 2 (MSH2 clone; FE11), MutS homolog 6 (MSH6 clone; EP49) and post-meiotic segregation 1 homolog 2 (PMS2 clone; EP51), and the DAKO EnVision system, as previously described (29). All antibodies and detection systems were purchased from Agilent Technologies, Inc. The Autostainer Link 48 and PT link (Agilent Technologies, Inc.) were used for the automated immunostaining system. All IHC results were evaluated using a light microscope.

Comparison of mutations between HAK-1A and HAK-1B, which were established from a single nodule. We compared the mutation number and type of HAK-1A and HAK-1B, which were established from different histological grades of a single nodule.

Fusion gene analysis. The target regions were enriched from RNA samples with The Archer® FusionPlex® Oncology Research Kit (Illumina, Inc.), and the sequencing was performed by using the Illumina NextSeq (Illumina, Inc.). We performed the Archer™ Analysis as the subsequent bioinformatics analysis for evaluating the quality of the read sequences, cleaning the sequences, mapping them to the reference sequence, and searching for fusion genes.

Effects of lenvatinib on proliferation of liver cell lines in vitro. These data were obtained from previous experiments as we reported (30). We reassessed the date based on fibroblast growth factor-19 (FGF-19) amplification. Detailed procedures are described in our previous report (29). Briefly, the cells (2-10×103 cells per well) were seeded in 96-well plates (Thermo Fisher Science, Roskilde, Denmark), cultured for 24 h, and the culture medium was changed to a new medium with or without lenvatinib at 1.875, 3.75, 7.5, 15, and 30 μM. The 50% inhibitory concentration (IC50) for each cell line was estimated after 72 h of culture with lenvatinib, which was supplied from Eisai, Tokyo Japan. We conducted the same experiment three times.

Results

Mutational landscape of representative gene variants in 13 liver cancer cell lines compared with HCC primary tumors. Representative genetic alterations, TMB, clinical correlations, and comparison of genetic alterations in human samples which were obtained from the public database are shown in Figure 1. Mutations in TP53, HMCN1, PCLO, HYDIN, APOB, EYS, AXIN1, ARID1A, ARID2, NEF2L2, and TSC2 were found in 11, 5, 4, 4, 3, 3, 2, 2, 1, 1, and 1 cell line(s), respectively. Details of the TP53 variants are shown in in Table II. Other rare genetic mutations, such as HRAS, GNAS, ALK, RET, and ROS1 were also observed. CTNNB1 mutation, which is one of the most frequently observed mutations in human HCC, was not identified in any of the cell lines. FGF19 amplification was observed in 4 cell lines. The cell lines with FGF19 amplification were stemmed from one well differentiated, one moderately to poorly differentiated, one poorly differentiated, and one sarcomatous HCC.

Figure 1.
Figure 1.

Mutational landscape of representative gene variants in 13 liver cancer cell lines compared with HCC primary tumors. Top panel shows the total mutation rate for each cell line. The heatmap represents mutations and copy number alteration in 13 liver cancer cell lines. On the left, histograms show a comparison of gene alteration frequency between 13 liver cancer cell lines and HCC (Fisher’s exact test, *p<0.05, **p<0.01, ***p<0.0001). HCC: Hepatocellular carcinoma; CHC: combined hepatocellular-cholangiocarcinoma.

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Table II.

TP53 mutation status of 12 cell lines.

Summary of genetic alterations of 13 liver cancer cell lines. Types of genetic alteration in 13 liver cancer cell lines are shown in Figure 2. Most of them were the missense variant and account for approximately 80% in each cell. This was followed by the frameshift variant and/or stop gain variant.

Figure 2.
Figure 2.

Summary of genetic alterations of 13 liver cancer cell lines. Although various types of mutations were observed, most mutations were of the missense variant type, followed by the frameshift variant and stop gain variant.

Morphological assessment of original tumor. Of 11 HCCs, six, four, and one nodule(s) demonstrated conventional, macrotrabecular massive (MTM), and sarcomatous type, respectively. All HCCs showing the MTM pattern had TP53 mutation (Figure 1 and Figure 3).

Figure 3.
Figure 3.

Morphological findings of a selection of original tumors. Original tumors of KYN-1 (A), KYN-2 (B), KYN-3 (C), and HAK6 (D) cell lines showing a macrotrabecular massive pattern.

Comparison of mutations between HAK-1A and HAK-1B, which were established from a single nodule. The association between morphological findings of the original tumor and gene mutations is shown in Figure 4. The number of mutations was 247 and 251 in HAK1A and HAK1B, respectively. Out of these mutations, 184 (approximately 75%) mutations were identical in HAK1A and HAK1B.

Figure 4.
Figure 4.

Morphological features of the original tumors of HAK-1A and HAK-1B cells. (A) Panoramic view of the original tumor (hematoxylin and eosin staining). The nodule is composed of a three-layered structure with a different histological grade in each layer. The areas surrounded by the red dotted line, with the light green dotted line and with the blue dotted line consist of well differentiated HCC, well differentiated HCC with fatty change, and poorly differentiated HCC, respectively. (B) Higher magnification of original part of HAK-1A. (C) Higher magnification of original part of HAK-1B. (D) Comparison of mutation number in HAK-1A and HAK-1B. Approximately 75% of genes were identical in HAK-1A and HAK-1B. HCC: Hepatocellular carcinoma.

Tumor mutation burden of HCC cell lines. The TMB ranged from 4.1 to 53.4 mutations/Mb (Figure 1). The TMB of 11 cell lines ranged from 4.1 to 7.9/Mb, whereas that of KYN-2 (HCC cell line) and KMCH-2 (cHCC-CCA cell line) was 39.7 mutations/Mb and 53.4 mutations/Mb, respectively. KYN-2 possessed the mutation of polymerase epsilon (POLE) pS297Y, which was defined as likely oncogenic/likely loss-of-function (31), leading to ultra-high mutation rates. KMCH-2 possessed the MLH1 P469fs mutation, which is likely oncogenic/likely loss-of-function (32), causing the recurrent alteration by deletion and mutation in various cancer types. To examine if MLH1 protein expression was retained in KMCH-2, we conducted IHC for MMR associated proteins. Microphotographs of IHC are shown in Figure 4. MLH1 and PMS2 expressions were lost (Figure 5A and 5B), while MSH2 and MSH6 expressions were retained (Figure 5C and 5D), which is a representative pattern of loss-of-function of MLH1.

Figure 5.
Figure 5.

Immunohistochemical staining for DNA mismatch repair protein using tissues obtained from the KMCH-2 mouse xenograft. MLH1 (A) and PMS2 (B) protein expression was undetected in tumor cells. Both MLH1 (A) and PMS2 (B) protein expression was detected in stromal cells. MSH2 (C) and MSH6 (D) protein expression was retained in tumor cells.

Fusion gene analysis. ADCK4::NUMBL, AXL::HNRNPUL1, ERBB2::GSE1, and TECR:: PKN1 were found in 8, 2, 2, and 1 cell line(s), respectively. Detail information was described in Table III.

View this table:
Table III.

Fusion genes of cell lines.

Effects of lenvatinib on the proliferation of liver cell lines in vitro. The medians of IC50 with and without FGF-19 amplification cell lines were 11.4 and 34.1 mM, respectively. The IC50 of FGF-19 amplification cell lines was significantly lower than those that lacked FGF-19 amplification cell lines (Table IV, p<0.01). We conducted the same experiment three times and obtained the same tendencies. Representative results are described herein.

View this table:
Table IV.

IC50 for lenvatinib.

Discussion

In this study, we conducted comprehensive genetic analyses in 13 primary liver cancer cell lines, which had been established and maintained in our Department. We found the following: i) The morphology of the original tumor showed a correlation with the pattern of genetic mutations; ii) eleven cell lines had TP53 mutation and no cell lines had the CTNNB1 mutation; iii) two cell lines showed an extremely high tumor mutation burden; iv) two cell lines, that had been established from different parts of a single nodule, shared approximately 75% of gene mutations, suggesting these could stem from the same clone; v) some novel fusion genes were identified; and vi) cell lines with FGF-19 amplification were susceptive to lenvatinib.

In human HCC, the most frequent mutations and chromosome alterations were identified in TERT promoter, CTNNB1, TP53, AXIN1, ARID1A, NFE2L2, ARID2, and RPS6KA3 (27, 33-37). However, CTNNB1 mutation was less frequent, and TP53 mutation was more common in cell lines compared to clinical samples, consistent with previous reports (38, 39). The precise mechanism is elusive; however, HCC with TP53 mutation may have resistance to severe conditions in-vitro. Indeed, we found that four cell lines were established from MTM-HCC, which is closely associated with TP53 mutation and carbonic anhydrase-IX (CA-IX) expression (40, 41). CA-IX is an enzyme involved in lowering pH and is induced by a hypoxic condition (42, 43), indicating that our speculation could be plausible.

In general, TMB of HCC was low and the cases with high TMB are extremely rare (44). To date, TMB of cHCC-CCA has not been reported. TMB of 11 cell lines was less than 10 mutations/Mb, whereas that of two KYN-2 and KMCH-2 was 39.7 mutations/Mb and 53.4 mutations/Mb, respectively. Two cell lines, KYN-2 and KMCH-2, have pathogenic variants in POLE and MLH1, respectively.

POLE encodes the catalytic subunit of DNA polymerase epsilon, an enzyme involved in DNA replication and repair. POLE mutations lead to ultra-high mutation rates (42). POLE mutations are frequently observed in colorectal cancer and endometrial cancer, and also found in various malignancies (45-48). A previous report demonstrated that only 4% of POLE/D mutations were found in advanced HCC (44).

MLH1, a tumor suppressor involved in DNA mismatch repair, is recurrently altered by deletion and mutation in various cancer types. Truncating mutations in the MLH1 result in premature codons and are associated with loss of MLH1 expression, preventing the protein’s ability to bind PMS2 (48-50). Loss of this interaction affects the ability of PMS2 to bind to DNA during damage resulting in impairment of the endonuclease function during DNA mismatch repair (MMR) (51-54). In our immunohistochemical stains for DNA mismatch, MMR proteins demonstrated the loss of MLH1 and PMS expression, compatible with MLH1 truncating mutation. In HCC and intrahepatic cholangiocarcinoma, the frequency of MLH1 mutation was less than 1% and 2.06%, respectively (55, 56). Also, a previous report documented that no DNA MMR protein deficiency was observed in 24 cHCC-CCA (56), indicating that DNA MMR protein deficiency is quite rare in primary liver cancers, especially cHCC-CCA. To date, commercially available cHCC-CCA cell lines have not been found. Therefore, the cHCC-CCA cell line, KMCH-2, with MLH1 mutation is extremely valuable.

In general, HCCs initially present as well-differentiated HCC, some of which is associated with a dysplastic nodule, premalignant lesion (57). When a well-differentiated HCC reaches a size of about 1.0-1.5 cm in diameter, less-differentiated cancerous tissues with greater proliferative activity evolve within it (57, 58). This phenomenon is called dedifferentiation pathologically. HAK-1A and HAK-1B were established from different histological grades of the same nodule (20). The former was derived from a well-differentiated part located in the outer layer; in contrast, the latter was derived from a poorly differentiated part located in the inner layer. These appearances are often called a “nodule-in-nodule”, which is convincing proof of multistep hepatocarcinogenesis. Although intensive studies have been conducted (59-62), the precise mechanism of dedifferentiation has not been fully elucidated. Takeda et al. conducted multiregional whole-genome sequencing of five HCCs with nodule-in-nodule appearance and revealed that genomic alterations associated with the TERT could be the key driver events in the formation of well-differentiated HCC and additional case-specific driver mutations accumulate during the progression phase (63). In their study, the number of somatic mutations was not necessarily increased in the dedifferentiated part (63). In our study, the number of mutations of HAK-1A and HAK-1B was almost comparable. Out of the mutations, approximately 75% was identical in two cell lines, indicating these two cell lines could evolve from the same clone.

We also detected several fusion genes in several cell lines. The ADCK4::NUMBL fusion gene was detected in cutaneous squamous cell carcinoma and shown to have proliferative activity (64). However, the biological consequence of the ADCK4::NUMBL fusion as well as the others in HCC is unclear.

We reassessed our previous data on the antiproliferative effects of lenvatinib based on FGF-19 amplification (30). Lenvatinib is a potent inhibitor of receptor tyrosine kinases, targeting vascular endothelial growth factor receptors 1-3, fibroblast growth factor receptors (FGFR1–4), KIT, and RET and is used for patients with advanced HCCs worldwide (65). FGF-19 is a ligand of FGFRs and its gene is amplified in some HCCs. Higher antiproliferative effects of lenvatinib were detected in cell lines with FGF-19 amplification, indicating that FGF-19 amplification could be a good candidate for predicting the efficacy of lenvatinib. This information is quite important as HCCs with FGF-19 amplification are known to be higher histological grades and show aggressive behavior.

Study limitations. First, we examined only the exome region, not the whole genome. Whole Genome Sequencing (WGS) approaches can be utilized to thoroughly investigate all types of genomic alterations in cancer. This helps in gaining a comprehensive understanding of the entire landscape of driver mutations and mutational signatures within cancer genomes. Furthermore, it aids in elucidating the functional or clinical implications of these unexplored genomic regions and mutational signatures (66). Second, two cell lines showed high TMB and we could only identify the mutation causing high TMB. However, we could not discriminate whether these mutations are somatic or germline mutations as we only examined the cancer cell line. Third, the longer cell lines are stored, there is a potential for their characteristics to change due to the artificial environment they are exposed to.

Rodent hepatocarcinogenesis models continue to be valuable tools for understanding molecular mechanisms in various pre-clinical settings. This is particularly true when these models closely mimic human pathology (67). Lambrecht et al. has recently revealed the suitability of spontaneous hepatocarcinogenesis development in Ppp2r5d KO mice as a new valuable murine hepatocarcinogenesis model that captures many characteristics of the human disease (68). It seems that a comprehensive analysis utilizing mouse models, cell lines, and clinical specimens is necessary to elucidate carcinogenesis and progression of hepatocellular carcinoma.

In conclusion, our study conducted whole exome sequence sequencing of 13 primary liver cancer cell lines established in our Department, using NGS. Correlations were observed between distinct tissue morphology and genetic mutations in some cell lines. Cell lines with clearly defined tissue morphology of the original tumor seem to be rare. Commercially available cell lines lack detailed information. Therefore, cell lines with comprehensive information such as morphological findings and patient records are highly valuable. The data obtained in this study are expected to contribute to the selection of cell lines when planning experimental designs.

Acknowledgements

We would like to thank Taiho pharmaceutical CO., LTD. for special supports and Ms. Fujiyoshi A for her excellent support.

Footnotes

  • Conflicts of Interest

    The Authors declare that no conflicts of interest exist.

  • Authors’ Contributions

    JA and HY conceived the idea of the study. JA and SO conducted experiments. JA developed the statistical analysis plan and conducted statistical analyses. All Authors contributed to the interpretation of the results. JA drafted the original manuscript. HY supervised the conduct of this study.

  • Received January 19, 2024.
  • Revision received February 16, 2024.
  • Accepted February 22, 2024.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Genetic Analyses of Primary Liver Cancer Cell Lines: Correspondence With Morphological Features of Original Tumors
JUN AKIBA, SACHIKO OGASAWARA, HIROHISA YANO
Cancer Genomics & Proteomics May 2024, 21 (3) 260-271; DOI: 10.21873/cgp.20445
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