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Published in: BMC Cancer 1/2021

Open Access 01-12-2021 | Hepatocellular Carcinoma | Research article

Identification of a five-immune gene model as an independent prognostic factor in hepatocellular carcinoma

Authors: Haitao Chen, Yueying Li, Shu-Yuan Xiao, Jianchun Guo

Published in: BMC Cancer | Issue 1/2021

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Abstract

Background

Hepatocellular carcinoma (HCC) is a common malignant tumor with a poor prognosis. We aimed to identify a new prognostic model of HCC based on differentially expressed (DE) immune genes.

Methods

The DE immune genes were identified based on an analysis of 374 cases of HCC and 50 adjacent non-tumor specimens from the Cancer Genome Atlas (TCGA) database. Univariate Cox analysis, Lasso regression, and multivariate Cox analysis were used to construct the model based on the training group. Survival analysis and the receiver operating characteristic (ROC) curves were used to evaluate model performance. The testing group and the entire group were subsequently used for validation of the model.

Results

A five-immune gene model consisted of HSPA4, ISG20L2, NDRG1, EGF, and IL17D was identified. Based on the model, the overall survival was significantly different between the high-risk and low-risk groups (P = 7.953e-06). The AUCs for the model at 1- and 3-year were 0.849 and 0.74, respectively. The reliability of the model was confirmed using the validation groups. The risk score was identified as an independent prognostic parameter and closely related to the content of immune cells from human HCC specimens.

Conclusion

We identified a five-immune gene model that can be used as an independent prognostic marker for HCC.
Appendix
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Literature
1.
go back to reference Cronin KA, Lake AJ, Scott S, Sherman RL, Noone AM, Howlader N, Henley SJ, Anderson RN, Firth AU, Ma J, et al. Annual report to the nation on the status of Cancer, part I: national cancer statistics. Cancer. 2018;124(13):2785–800.CrossRef Cronin KA, Lake AJ, Scott S, Sherman RL, Noone AM, Howlader N, Henley SJ, Anderson RN, Firth AU, Ma J, et al. Annual report to the nation on the status of Cancer, part I: national cancer statistics. Cancer. 2018;124(13):2785–800.CrossRef
2.
go back to reference Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.
3.
go back to reference Zongyi Y, Xiaowu L. Immunotherapy for hepatocellular carcinoma. Cancer Lett. 2019;470:8–17.CrossRef Zongyi Y, Xiaowu L. Immunotherapy for hepatocellular carcinoma. Cancer Lett. 2019;470:8–17.CrossRef
4.
go back to reference Zhang X, Li J, Ghoshal K, Fernandez S, Li L. Identification of a subtype of hepatocellular carcinoma with poor prognosis based on expression of genes within the glucose metabolic pathway. Cancers. 2019;11(12):2023.CrossRef Zhang X, Li J, Ghoshal K, Fernandez S, Li L. Identification of a subtype of hepatocellular carcinoma with poor prognosis based on expression of genes within the glucose metabolic pathway. Cancers. 2019;11(12):2023.CrossRef
5.
go back to reference Chen Q, Wang M, Wang M, Jin S, Xiao SY, Tian S. Expansile invasive growth pattern is definite evidence for the diagnosis of small hepatocellular carcinomas: a comparative study of 37 cases. Hum Pathol. 2018;80:130–7.CrossRef Chen Q, Wang M, Wang M, Jin S, Xiao SY, Tian S. Expansile invasive growth pattern is definite evidence for the diagnosis of small hepatocellular carcinomas: a comparative study of 37 cases. Hum Pathol. 2018;80:130–7.CrossRef
6.
go back to reference Zhu R, Yang X, Guo W, Xu XJ, Zhu L. An eight-mRNA signature predicts the prognosis of patients with bladder urothelial carcinoma. Peer J. 2019;7:e7836.CrossRef Zhu R, Yang X, Guo W, Xu XJ, Zhu L. An eight-mRNA signature predicts the prognosis of patients with bladder urothelial carcinoma. Peer J. 2019;7:e7836.CrossRef
7.
go back to reference Siu LL, Ivy SP, Dixon EL, Gravell AE, Reeves SA, Rosner GL. Challenges and opportunities in adapting clinical trial Design for Immunotherapies. Clin Cancer Res. 2017;23(17):4950–8.CrossRef Siu LL, Ivy SP, Dixon EL, Gravell AE, Reeves SA, Rosner GL. Challenges and opportunities in adapting clinical trial Design for Immunotherapies. Clin Cancer Res. 2017;23(17):4950–8.CrossRef
8.
go back to reference Tai D, Choo SP, Chew V. Rationale of immunotherapy in hepatocellular carcinoma and its potential biomarkers. Cancers. 2019;11(12):1926.CrossRef Tai D, Choo SP, Chew V. Rationale of immunotherapy in hepatocellular carcinoma and its potential biomarkers. Cancers. 2019;11(12):1926.CrossRef
9.
go back to reference Joerger M, Guller U, Bastian S, Driessen C, von Moos R. Prolonged tumor response associated with sequential immune checkpoint inhibitor combination treatment and regorafenib in a patient with advanced pretreated hepatocellular carcinoma. J Gastrointest Oncol. 2019;10(2):373–8.CrossRef Joerger M, Guller U, Bastian S, Driessen C, von Moos R. Prolonged tumor response associated with sequential immune checkpoint inhibitor combination treatment and regorafenib in a patient with advanced pretreated hepatocellular carcinoma. J Gastrointest Oncol. 2019;10(2):373–8.CrossRef
10.
go back to reference Agdashian D, ElGindi M, Xie C, Sandhu M, Pratt D, Kleiner DE, Figg WD, Rytlewski JA, Sanders C, Yusko EC, et al. The effect of anti-CTLA4 treatment on peripheral and intra-tumoral T cells in patients with hepatocellular carcinoma. Cancer Immunol Immunother. 2019;68(4):599–608.CrossRef Agdashian D, ElGindi M, Xie C, Sandhu M, Pratt D, Kleiner DE, Figg WD, Rytlewski JA, Sanders C, Yusko EC, et al. The effect of anti-CTLA4 treatment on peripheral and intra-tumoral T cells in patients with hepatocellular carcinoma. Cancer Immunol Immunother. 2019;68(4):599–608.CrossRef
11.
go back to reference Liu F, Zeng G, Zhou S, He X, Sun N, Zhu X, Hu A. Blocking Tim-3 or/and PD-1 reverses dysfunction of tumor-infiltrating lymphocytes in HBV-related hepatocellular carcinoma. Bull Cancer. 2018;105(5):493–501.CrossRef Liu F, Zeng G, Zhou S, He X, Sun N, Zhu X, Hu A. Blocking Tim-3 or/and PD-1 reverses dysfunction of tumor-infiltrating lymphocytes in HBV-related hepatocellular carcinoma. Bull Cancer. 2018;105(5):493–501.CrossRef
12.
go back to reference Zhou G, Sprengers D, Boor PPC, Doukas M, Schutz H, Mancham S, Pedroza-Gonzalez A, Polak WG, de Jonge J, Gaspersz M, et al. Antibodies against immune checkpoint molecules restore functions of tumor-infiltrating t cells in hepatocellular carcinomas. Gastroenterology. 2017;153(4):1107–1119.e1110.CrossRef Zhou G, Sprengers D, Boor PPC, Doukas M, Schutz H, Mancham S, Pedroza-Gonzalez A, Polak WG, de Jonge J, Gaspersz M, et al. Antibodies against immune checkpoint molecules restore functions of tumor-infiltrating t cells in hepatocellular carcinomas. Gastroenterology. 2017;153(4):1107–1119.e1110.CrossRef
13.
go back to reference Li W, Wang H, Ma Z, Zhang J, Ou-Yang W, Qi Y, Liu J. Multi-omics analysis of microenvironment characteristics and immune escape mechanisms of hepatocellular carcinoma. Front Oncol. 2019;9:1019.CrossRef Li W, Wang H, Ma Z, Zhang J, Ou-Yang W, Qi Y, Liu J. Multi-omics analysis of microenvironment characteristics and immune escape mechanisms of hepatocellular carcinoma. Front Oncol. 2019;9:1019.CrossRef
14.
go back to reference Dong Z, Chen Y, Yang C, Zhang M, Chen A, Yang J, Huang Y. STAT gene family mRNA expression and prognostic value in hepatocellular carcinoma. Onco Targets Ther. 2019;12:7175–91.CrossRef Dong Z, Chen Y, Yang C, Zhang M, Chen A, Yang J, Huang Y. STAT gene family mRNA expression and prognostic value in hepatocellular carcinoma. Onco Targets Ther. 2019;12:7175–91.CrossRef
15.
go back to reference Mei S, Meyer CA, Zheng R, Qin Q, Wu Q, Jiang P, Li B, Shi X, Wang B, Fan J, et al. Cistrome Cancer: a web resource for integrative gene regulation modeling in Cancer. Cancer Res. 2017;77(21):e19–22.CrossRef Mei S, Meyer CA, Zheng R, Qin Q, Wu Q, Jiang P, Li B, Shi X, Wang B, Fan J, et al. Cistrome Cancer: a web resource for integrative gene regulation modeling in Cancer. Cancer Res. 2017;77(21):e19–22.CrossRef
16.
go back to reference Bhattacharya S, Andorf S, Gomes L, Dunn P, Schaefer H, Pontius J, Berger P, Desborough V, Smith T, Campbell J, et al. ImmPort: disseminating data to the public for the future of immunology. Immunol Res. 2014;58(2–3):234–9.CrossRef Bhattacharya S, Andorf S, Gomes L, Dunn P, Schaefer H, Pontius J, Berger P, Desborough V, Smith T, Campbell J, et al. ImmPort: disseminating data to the public for the future of immunology. Immunol Res. 2014;58(2–3):234–9.CrossRef
17.
go back to reference Wang Z, Gao L, Guo X, Feng C, Lian W, Deng K, Xing B. Development of a Nomogram with alternative splicing signatures for predicting the prognosis of Glioblastoma: a study based on large-scale sequencing data. Front Oncol. 2020;10:1257.CrossRef Wang Z, Gao L, Guo X, Feng C, Lian W, Deng K, Xing B. Development of a Nomogram with alternative splicing signatures for predicting the prognosis of Glioblastoma: a study based on large-scale sequencing data. Front Oncol. 2020;10:1257.CrossRef
18.
go back to reference Chen P, He J, Ye H, Jiang S, Li Y, Li X, Wan J. Comprehensive analysis of prognostic alternative splicing signatures in endometrial Cancer. Front Genet. 2020;11:456.CrossRef Chen P, He J, Ye H, Jiang S, Li Y, Li X, Wan J. Comprehensive analysis of prognostic alternative splicing signatures in endometrial Cancer. Front Genet. 2020;11:456.CrossRef
19.
go back to reference Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D, Barrette T, Pandey A, Chinnaiyan AM. ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia. 2004;6(1):1–6.CrossRef Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D, Barrette T, Pandey A, Chinnaiyan AM. ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia. 2004;6(1):1–6.CrossRef
20.
go back to reference Colwill K, Gräslund S. A roadmap to generate renewable protein binders to the human proteome. Nat Methods. 2011;8(7):551–8.CrossRef Colwill K, Gräslund S. A roadmap to generate renewable protein binders to the human proteome. Nat Methods. 2011;8(7):551–8.CrossRef
21.
go back to reference Newman AM, Liu CL, Green MR, Gentles AJ, Feng W, Xu Y, Hoang CD, Diehn M, Alizadeh AA. Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015;12(5):453–7.CrossRef Newman AM, Liu CL, Green MR, Gentles AJ, Feng W, Xu Y, Hoang CD, Diehn M, Alizadeh AA. Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015;12(5):453–7.CrossRef
22.
go back to reference Li B, Severson E, Pignon JC, Zhao H, Li T, Novak J, Jiang P, Shen H, Aster JC, Rodig S, et al. Comprehensive analyses of tumor immunity: implications for cancer immunotherapy. Genome Biol. 2016;17(1):174.CrossRef Li B, Severson E, Pignon JC, Zhao H, Li T, Novak J, Jiang P, Shen H, Aster JC, Rodig S, et al. Comprehensive analyses of tumor immunity: implications for cancer immunotherapy. Genome Biol. 2016;17(1):174.CrossRef
23.
go back to reference Kaneko Y, Kimura T, Kishishita M, Noda Y, Fujita J. Cloning of apg-2 encoding a novel member of heat shock protein 110 family. Gene. 1997;189(1):19–24.CrossRef Kaneko Y, Kimura T, Kishishita M, Noda Y, Fujita J. Cloning of apg-2 encoding a novel member of heat shock protein 110 family. Gene. 1997;189(1):19–24.CrossRef
24.
go back to reference Gotoh K, Nonoguchi K, Higashitsuji H, Kaneko Y, Sakurai T, Sumitomo Y, Itoh K, Subjeck JR, Fujita J. Apg-2 has a chaperone-like activity similar to Hsp110 and is overexpressed in hepatocellular carcinomas. FEBS Lett. 2004;560(1–3):19–24.CrossRef Gotoh K, Nonoguchi K, Higashitsuji H, Kaneko Y, Sakurai T, Sumitomo Y, Itoh K, Subjeck JR, Fujita J. Apg-2 has a chaperone-like activity similar to Hsp110 and is overexpressed in hepatocellular carcinomas. FEBS Lett. 2004;560(1–3):19–24.CrossRef
25.
go back to reference Duzgun MB, Theofilatos K, Georgakilas AG, Pavlopoulou A. A Bioinformatic approach for the identification of molecular determinants of resistance/sensitivity to Cancer thermotherapy. Oxidative Med Cell Longev. 2019;2019:4606219.CrossRef Duzgun MB, Theofilatos K, Georgakilas AG, Pavlopoulou A. A Bioinformatic approach for the identification of molecular determinants of resistance/sensitivity to Cancer thermotherapy. Oxidative Med Cell Longev. 2019;2019:4606219.CrossRef
26.
go back to reference Cheng J, Xie HY, Xu X, Wu J, Wei X, Su R, Zhang W, Lv Z, Zheng S, Zhou L. NDRG1 as a biomarker for metastasis, recurrence and of poor prognosis in hepatocellular carcinoma. Cancer Lett. 2011;310(1):35–45.CrossRef Cheng J, Xie HY, Xu X, Wu J, Wei X, Su R, Zhang W, Lv Z, Zheng S, Zhou L. NDRG1 as a biomarker for metastasis, recurrence and of poor prognosis in hepatocellular carcinoma. Cancer Lett. 2011;310(1):35–45.CrossRef
27.
go back to reference Luo Q, Wang CQ, Yang LY, Gao XM, Sun HT, Zhang Y, Zhang KL, Zhu Y, Zheng Y, Sheng YY, et al. FOXQ1/NDRG1 axis exacerbates hepatocellular carcinoma initiation via enhancing crosstalk between fibroblasts and tumor cells. Cancer Lett. 2018;417:21–34.CrossRef Luo Q, Wang CQ, Yang LY, Gao XM, Sun HT, Zhang Y, Zhang KL, Zhu Y, Zheng Y, Sheng YY, et al. FOXQ1/NDRG1 axis exacerbates hepatocellular carcinoma initiation via enhancing crosstalk between fibroblasts and tumor cells. Cancer Lett. 2018;417:21–34.CrossRef
28.
go back to reference Lu WJ, Chua MS, So SK. Suppressing N-Myc downstream regulated gene 1 reactivates senescence signaling and inhibits tumor growth in hepatocellular carcinoma. Carcinogenesis. 2014;35(4):915–22.CrossRef Lu WJ, Chua MS, So SK. Suppressing N-Myc downstream regulated gene 1 reactivates senescence signaling and inhibits tumor growth in hepatocellular carcinoma. Carcinogenesis. 2014;35(4):915–22.CrossRef
29.
go back to reference Zhu Y, Zhou C, He Q. High miR-139-3p expression predicts a better prognosis for hepatocellular carcinoma: a pooled analysis. J Int Med Res. 2019;47(1):383–90.CrossRef Zhu Y, Zhou C, He Q. High miR-139-3p expression predicts a better prognosis for hepatocellular carcinoma: a pooled analysis. J Int Med Res. 2019;47(1):383–90.CrossRef
30.
go back to reference Junttila MR, de Sauvage FJ. Influence of tumour micro-environment heterogeneity on therapeutic response. Nature. 2013;501(7467):346–54.CrossRef Junttila MR, de Sauvage FJ. Influence of tumour micro-environment heterogeneity on therapeutic response. Nature. 2013;501(7467):346–54.CrossRef
31.
go back to reference McGranahan N, Furness AJ, Rosenthal R, Ramskov S, Lyngaa R, Saini SK, Jamal-Hanjani M, Wilson GA, Birkbak NJ, Hiley CT, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science. 2016;351(6280):1463–9.CrossRef McGranahan N, Furness AJ, Rosenthal R, Ramskov S, Lyngaa R, Saini SK, Jamal-Hanjani M, Wilson GA, Birkbak NJ, Hiley CT, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science. 2016;351(6280):1463–9.CrossRef
32.
go back to reference Chen QF, Li W, Wu PH, Shen LJ, Huang ZL. Significance of tumor-infiltrating immunocytes for predicting prognosis of hepatitis B virus-related hepatocellular carcinoma. World J Gastroenterol. 2019;25(35):5266–82.CrossRef Chen QF, Li W, Wu PH, Shen LJ, Huang ZL. Significance of tumor-infiltrating immunocytes for predicting prognosis of hepatitis B virus-related hepatocellular carcinoma. World J Gastroenterol. 2019;25(35):5266–82.CrossRef
33.
go back to reference Ma J, Zheng B, Goswami S, Meng L, Zhang D, Cao C, Li T, Zhu F, Ma L, Zhang Z, et al. PD1(hi) CD8(+) T cells correlate with exhausted signature and poor clinical outcome in hepatocellular carcinoma. J Immunother Cancer. 2019;7(1):331.CrossRef Ma J, Zheng B, Goswami S, Meng L, Zhang D, Cao C, Li T, Zhu F, Ma L, Zhang Z, et al. PD1(hi) CD8(+) T cells correlate with exhausted signature and poor clinical outcome in hepatocellular carcinoma. J Immunother Cancer. 2019;7(1):331.CrossRef
34.
go back to reference Ju Q, Li XM, Zhang H, Zhao YJ. BRCA1-associated protein is a potential prognostic biomarker and is correlated with immune infiltration in liver hepatocellular carcinoma: a pan-Cancer analysis. Front Mol Biosci. 2020;7:573619.CrossRef Ju Q, Li XM, Zhang H, Zhao YJ. BRCA1-associated protein is a potential prognostic biomarker and is correlated with immune infiltration in liver hepatocellular carcinoma: a pan-Cancer analysis. Front Mol Biosci. 2020;7:573619.CrossRef
35.
go back to reference Sia D, Jiao Y, Martinez-Quetglas I, Kuchuk O, Villacorta-Martin C, Castro de Moura M, Putra J, Camprecios G, Bassaganyas L, Akers N, et al. Identification of an immune-specific class of hepatocellular carcinoma. Based Mol Features Gastroenterol. 2017;153(3):812–26. Sia D, Jiao Y, Martinez-Quetglas I, Kuchuk O, Villacorta-Martin C, Castro de Moura M, Putra J, Camprecios G, Bassaganyas L, Akers N, et al. Identification of an immune-specific class of hepatocellular carcinoma. Based Mol Features Gastroenterol. 2017;153(3):812–26.
36.
go back to reference Xiao SY, Wang HL, Hart J, Fleming D, Beard MR. cDNA arrays and immunohistochemistry identification of CD10/CALLA expression in hepatocellular carcinoma. Am J Pathol. 2001;159(4):1415–21.CrossRef Xiao SY, Wang HL, Hart J, Fleming D, Beard MR. cDNA arrays and immunohistochemistry identification of CD10/CALLA expression in hepatocellular carcinoma. Am J Pathol. 2001;159(4):1415–21.CrossRef
37.
go back to reference Souza T, Jennen D, van Delft J, van Herwijnen M, Kyrtoupolos S, Kleinjans J. New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016;90(6):1449–58.CrossRef Souza T, Jennen D, van Delft J, van Herwijnen M, Kyrtoupolos S, Kleinjans J. New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016;90(6):1449–58.CrossRef
38.
go back to reference Zhang C, Peng L, Zhang Y, Liu Z, Li W, Chen S, Li G. The identification of key genes and pathways in hepatocellular carcinoma by bioinformatics analysis of high-throughput data. Med Oncol. 2017;34(6):101.CrossRef Zhang C, Peng L, Zhang Y, Liu Z, Li W, Chen S, Li G. The identification of key genes and pathways in hepatocellular carcinoma by bioinformatics analysis of high-throughput data. Med Oncol. 2017;34(6):101.CrossRef
Metadata
Title
Identification of a five-immune gene model as an independent prognostic factor in hepatocellular carcinoma
Authors
Haitao Chen
Yueying Li
Shu-Yuan Xiao
Jianchun Guo
Publication date
01-12-2021
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2021
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-021-08012-2

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