Correlations between genomic and transcriptome characteristics and immune in hepatocellular carcinoma

Abstract

Abstract:

Hepatocellular carcinoma is a common malignant tumor in China, and its global incidence continues to rise and the mortality rate is high. Aberrations in the liver genome lead to malignant transformation of cells and the development of hepatocellular carcinoma, which are also potential therapeutic targets. Different immune cell components in the hepatocellular carcinoma microenvironment, such as tumor-associated macrophages, neutrophils, can promote tumor progression, and cytotoxic T lymphocytes can destroy tumor cells. Different characteristic gene phenotypes in cells can promote or inhibit immune tolerance, which can explain the potential reasons for the sensitivity or resistance of hepatocellular carcinoma patients to immunotherapy, and provide a reference for the exploration of new immunotherapy targets. Further deepening the understanding of the genomic and transcriptomic features in hepatocellular carcinoma and its correlation with immunotherapy can provide new ideas for clinical diagnosis and treatment.

Key words:Carcinoma, hepatocellular,Liver cirrhosis,Immunotherapy

Sun Xiaoke, Yang Yu. Correlations between genomic and transcriptome characteristics and immune in hepatocellular carcinoma[J]. Journal of International Oncology, 2022, 49(5): 302-306.

Figures/Tables1

基因	基因组改变	占比	生物学途径
TERT^{[ 12 ⇓ - 14 ]}	启动子突变	50%~60%	端粒维持
TERT^{[ 13 - 14 ]}	扩增	6%	端粒维持
TERT^{[ 13 - 14 ]}	易位	3%	端粒维持
TP53^{[ 13 - 14 ]}	失活突变	15%~40%	细胞周期控制
CDKN2A^{[ 14 ]}	失活突变	2%~9%	细胞周期控制
CCND1^{[ 14 ]}	扩增	7%	细胞周期控制
CTNNB1^{[ 12 ⇓ - 14 ]}	激活突变	10%~35%	Wnt/β-连环蛋白途径
AXIN1^{[ 13 - 14 ]}	失活突变	5%~15%	Wnt/β-连环蛋白途径
FGF19^{[ 13 - 14 ]}	扩增	5%~10%	PI3K/AKT-mTOR途径
RPS6KA3^{[ 13 - 14 ]}	失活突变	2%~9%	PI3K/AKT-mTOR途径
VEGFA^{[ 13 - 14 ]}	扩增	4%	PI3K/AKT-mTOR途径
ARID1A^{[ 12 ⇓ - 14 ]}	失活突变	5%~17%	染色质重塑
ARID2^{[ 13 - 14 ]}	失活突变	3%~18%	染色质重塑
NFE2L2^{[ 13 - 14 ]}	激活突变	3%~6%	氧化应激途径
KEAP1^{[ 13 - 14 ]}	失活突变	2%~8%	氧化应激途径

References36

[1]	Cheu JW, Wong CC. Mechanistic rationales guiding combination hepatocellular carcinoma therapies involving immune checkpoint inhibitors[J]. Hepatology, 2021, 74(4): 2264-2276. DOI: 10.1002/hep.31840. doi:10.1002/hep.31840
[2]	O'Rourke JM, Sagar VM, Shah T, et al. Carcinogenesis on the background of liver fibrosis: implications for the management of hepatocellular cancer[J]. World J Gastroenterol, 2018, 24(39): 4436-4447. DOI: 10.3748/wjg.v24.i39.4436. doi:10.3748/wjg.v24.i39.4436
[3]	He Y, Lu M, Che J, et al. Biomarkers and future perspectives for hepatocellular carcinoma immunotherapy[J]. Front Oncol, 2021, 11: 716844. DOI: 10.3389/fonc.2021.716844. doi:10.3389/fonc.2021.716844
[4]	El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial[J]. Lancet, 2017, 389(10088): 2492-2502. DOI: 10.1016/S0140-6736(17)31046-2. doi:S0140-6736(17)31046-2pmid:28434648
[5]	Brunner SF, Roberts ND, Wylie LA, et al. Somatic mutations and clonal dynamics in healthy and cirrhotic human liver[J]. Nature, 2019, 574(7779): 538-542. DOI: 10.1038/s41586-019-1670-9. doi:10.1038/s41586-019-1670-9
[6]	Müller M, Bird TG, Nault JC. The landscape of gene mutations in cirrhosis and hepatocellular carcinoma[J]. J Hepatol, 2020, 72(5): 990-1002. DOI: 10.1016/j.jhep.2020.01.019. doi:10.1016/j.jhep.2020.01.019
[7]	Llovet JM, Zucman-Rossi J, Pikarsky E, et al. Hepatocellular carcinoma[J]. Nat Rev Dis Primers, 2016, 2: 16018. DOI: 10.1038/nrdp.2016.18. doi:10.1038/nrdp.2016.18pmid:27158749
[8]	Torrecilla S, Sia D, Harrington AN, et al. Trunk mutational events present minimal intra- and inter-tumoral heterogeneity in hepatocellular carcinoma[J]. J Hepatol, 2017, 67(6): 1222-1231. DOI: 10.1016/j.jhep.2017.08.013. doi:S0168-8278(17)32252-3pmid:28843658
[9]	Zhu M, Lu T, Jia Y, et al. Somatic mutations increase hepatic clonal fitness and regeneration in chronic liver disease[J]. Cell, 2019, 177(3): 608-621.e12. DOI: 10.1016/j.cell.2019.03.026. doi:10.1016/j.cell.2019.03.026
[10]	Harding JJ, Nandakumar S, Armenia J, et al. Prospective genoty-ping of hepatocellular carcinoma: clinical implications of next-generation sequencing for matching patients to targeted and immune therapies[J]. Clin Cancer Res, 2019, 25(7): 2116-2126. DOI: 10.1158/1078-0432.CCR-18-2293. doi:10.1158/1078-0432.CCR-18-2293pmid:30373752
[11]	Letouzé E, Shinde J, Renault V, et al. Mutational signatures reveal the dynamic interplay of risk factors and cellular processes during liver tumorigenesis[J]. Nat Commun, 2017, 8(1): 1315. DOI: 10.1038/s41467-017-01358-x. doi:10.1038/s41467-017-01358-xpmid:29101368
[12]	Nault JC, Martin Y, Caruso S, et al. Clinical impact of genomic diversity from early to advanced hepatocellular carcinoma[J]. Hepatology, 2020, 71(1): 164-182. DOI: 10.1002/hep.30811. doi:10.1002/hep.30811
[13]	Schulze K, Imbeaud S, Letouzé E, et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets[J]. Nat Genet, 2015, 47(5): 505-511. DOI: 10.1038/ng.3252. doi:10.1038/ng.3252
[14]	Totoki Y, Tatsuno K, Covington KR, et al. Trans-ancestry mutational landscape of hepatocellular carcinoma genomes[J]. Nat Genet, 2014, 46(12): 1267-1273. DOI: 10.1038/ng.3126. doi:10.1038/ng.3126
[15]	Di Agostino S. The impact of mutant p53 in the non-coding RNA world[J]. Biomolecules, 2020, 10(3): 472. DOI: 10.3390/biom 10030472. doi:10.3390/biom 10030472
[16]	Takai A, Dang HT, Wang XW. Identification of drivers from cancer genome diversity in hepatocellular carcinoma[J]. Int J Mol Sci, 2014, 15(6): 11142-11160. DOI: 10.3390/ijms150611142. doi:10.3390/ijms150611142
[17]	Krutsenko Y, Singhi AD, Monga SP. β-catenin activation in hepatocellular cancer: implications in biology and therapy[J]. Cancers (Basel), 2021, 13(8): 1830. DOI: 10.3390/cancers13081830. doi:10.3390/cancers13081830
[18]	Li J, Quan H, Liu Q, et al. Alterations of axis inhibition protein 1 (AXIN1) in hepatitis B virus-related hepatocellular carcinoma and overexpression of AXIN1 induces apoptosis in hepatocellular cancer cells[J]. Oncol Res, 2013, 20(7): 281-288. DOI: 10.3727/096504013x13639794277608. doi:10.3727/096504013x13639794277608
[19]	Kurebayashi Y, Ojima H, Tsujikawa H, et al. Landscape of immune microenvironment in hepatocellular carcinoma and its additional impact on histological and molecular classification[J]. Hepatology, 2018, 68(3): 1025-1041. DOI: 10.1002/hep.29904. doi:10.1002/hep.29904pmid:29603348
[20]	Ovais M, Guo M, Chen C. Tailoring nanomaterials for targeting tumor-associated macrophages[J]. Adv Mater, 2019, 31(19): e1808303. DOI: 10.1002/adma.201808303. doi:10.1002/adma.201808303
[21]	Pose E, Coll M, Martínez-Sánchez C, et al. Programmed death ligand 1 is overexpressed in liver macrophages in chronic liver diseases, and its blockade improves the antibacterial activity against infections[J]. Hepatology, 2021, 74(1): 296-311. DOI: 10.1002/hep.31644. doi:10.1002/hep.31644
[22]	Mayadas TN, Cullere X, Lowell CA. The multifaceted functions of neutrophils[J]. Annu Rev Pathol, 2014, 9: 181-218. DOI: 10.1146/annurev-pathol-020712-164023. doi:10.1146/annurev-pathol-020712-164023pmid:24050624
[23]	Nishida N, Kudo M. Oncogenic signal and tumor microenvironment in hepatocellular carcinoma[J]. Oncology, 2017, 93(Suppl-1): 160-164. DOI: 10.1159/000481246. doi:10.1159/000481246
[24]	Ringelhan M, Pfister D, O’Connor T, et al. The immunology of hepatocellular carcinoma[J]. Nat Immunol, 2018, 19(3): 222-232. DOI: 10.1038/s41590-018-0044-z. doi:10.1038/s41590-018-0044-zpmid:29379119
[25]	Huang Y, Wang FM, Wang T, et al. Tumor-infiltrating FoxP3⁺tregs and CD8⁺T cells affect the prognosis of hepatocellular carcinoma patients[J]. Digestion, 2012, 86(4): 329-337. DOI: 10.1159/000342801. doi:10.1159/000342801pmid:23207161
[26]	McGovern BH, Golan Y, Lopez M, et al. The impact of cirrhosis on CD4⁺T cell counts in HIV-seronegative patients[J]. Clin Infect Dis, 2007, 44(3): 431-437. DOI: 10.1086/509580. doi:10.1086/509580pmid:17205454
[27]	Zheng C, Zheng L, Yoo JK, et al. Landscape of infiltrating T cells in liver cancer revealed by single-cell sequencing[J]. Cell, 2017, 169(7): 1342-1356.e16. DOI: 10.1016/j.cell.2017.05.035. doi:10.1016/j.cell.2017.05.035
[28]	Wang JC, Livingstone AM. Cutting edge: CD4⁺T cell help can be essential for primary CD8⁺T cell responses in vivo[J]. J Immunol, 2003, 171(12): 6339-6343. DOI: 10.4049/jimmunol.171.12.6339. doi:10.4049/jimmunol.171.12.6339
[29]	Cai L, Zhang Z, Zhou L, et al. Functional impairment in circulating and intrahepatic NK cells and relative mechanism in hepatocellular carcinoma patients[J]. Clin Immunol, 2008, 129(3): 428-437. DOI: 10.1016/j.clim.2008.08.012. doi:10.1016/j.clim.2008.08.012
[30]	Tcyganov E, Mastio J, Chen E, et al. Plasticity of myeloid-derived suppressor cells in cancer[J]. Curr Opin Immunol, 2018, 51: 76-82. DOI: 10.1016/j.coi.2018.03.009. doi:S0952-7915(17)30109-7pmid:29547768
[31]	Liu Z, Zhang Y, Shi C, et al. A novel immune classification reveals distinct immune escape mechanism and genomic altera-tions: implications for immunotherapy in hepatocellular carcinoma[J]. J Transl Med, 2021, 19(1): 5. DOI: 10.1186/s12967-020-02697-y. doi:10.1186/s12967-020-02697-y
[32]	Pinyol R, Sia D, Llovet JM. Immune exclusion-Wnt/CTNNB1 class predicts resistance to immunotherapies in HCC[J]. Clin Cancer Res, 2019, 25(7): 2021-2023. DOI: 10.1158/1078-0432.CCR-18-3778. doi:10.1158/1078-0432.CCR-18-3778pmid:30617138
[33]	Choi M, Kadara H, Zhang J, et al. Mutation profiles in early-stage lung squamous cell carcinoma with clinical follow-up and correlation with markers of immune function[J]. Ann Oncol, 2017, 28(1): 83-89. DOI: 10.1093/annonc/mdw437. doi:10.1093/annonc/mdw437pmid:28177435
[34]	Shen J, Ju Z, Zhao W, et al. ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade[J]. Nat Med, 2018, 24(5): 556-562. DOI: 10.1038/s41591-018-0012-z. doi:10.1038/s41591-018-0012-z
[35]	Berger MF, Mardis ER. The emerging clinical relevance of geno-mics in cancer medicine[J]. Nat Rev Clin Oncol, 2018, 15(6): 353-365. DOI: 10.1038/s41571-018-0002-6. doi:10.1038/s41571-018-0002-6
[36]	Ou Q, Yu Y, Li A, et al. Association of survival and genomic mutation signature with immunotherapy in patients with hepatocellular carcinoma[J]. Ann Transl Med, 2020, 8(5): 230. DOI: 10.21037/atm.2020.01.32. doi:10.21037/atm.2020.01.32