Login Register Cart 0
Generic placeholder image

Current Cancer Drug Targets

Editor-in-Chief

ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Development of Chromatin Regulator-related Molecular Subtypes and a Signature to Predict Prognosis and Immunotherapeutic Response in Head and Neck Squamous Cell Carcinoma

Author(s): Juntao Huang*, Ziqian Xu, Zhenzhen Wang, Chongchang Zhou and Yi Shen*

Volume 24, Issue 8, 2024

Published on: 04 January, 2024

Page: [804 - 819] Pages: 16

DOI: 10.2174/0115680096274798231121053634

Price: $65

Abstract

Background: Chromatin regulators (CRs) serve as indispensable factors in tumor biological processes by influencing tumorigenesis and the immune microenvironment and have been identified in head and neck squamous cell carcinoma (HNSCC). Hence, CR-related genes (CRRGs) are considered potential biomarkers for predicting prognosis and immune infiltration in HNSCC. In this study, we established a novel signature for predicting the prognosis and immunotherapeutic response of HSNCC.

Methods: A total of 870 CRRGs were obtained according to previous studies. Subsequently, patients in the TCGA-HNSC cohort were divided into different clusters based on the expression of prognostic CRRGs. Kaplan‒Meier (K‒M) survival analysis was conducted to compare the prognosis in clusters, and the CIBERSORT and ssGSEA methods assessed the immune infiltration status. In addition, the differences in immunotherapeutic responses were determined based on the TICA database. Furthermore, the differentially expressed CRRGs between clusters were identified, and the predictive signature was established according to the results of univariate Cox, least absolute shrinkage and selection operator regression analysis, and multivariate Cox. The predictive effects of the risk model were evaluated according to the area under the receiver operating characteristic (ROC) curve (AUC) in both the training and external test cohorts. A nomogram was established, and survival comparisons, functional enrichment analyses, and immune infiltration status and clinical treatment assessments were performed. In addition, the hub gene network and related analysis were conducted with the Cytohubba application.

Results: Based on the expression of prognostic CRRGs, patients were divided into two clusters, in which Cluster 1 exhibited a better prognosis, more enriched immune infiltration, and a better immunotherapeutic response but exhibited chemotherapy sensitivity. The AUC values of the 1-, 3- and 5- year ROC curves for the risk model were 0.673, 0.732, and 0.692, respectively, as well as 0.645, 0.608, and 0.623 for the test set. In addition, patients in the low-risk group exhibited more immune cell enrichment and immune function activation, as well as a better immunotherapy response. The hub gene network indicated ACTN2 as the core gene differentially expressed between the two risk groups.

Conclusion: We identified molecular subtypes and established a novel predictive signature based on CRRGs. This effective CRRS system can possibly provide a novel research direction for exploring the correlation between CRs and HNSCC and requires further experimental validation.

« Previous Next »
Graphical Abstract

[1]
Chow, L.Q.M. Head and neck cancer. N. Engl. J. Med., 2020, 382(1), 60-72.
[http://dx.doi.org/10.1056/NEJMra1715715] [PMID: 31893516]
[2]
Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; 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.
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
[3]
Yuan, Z.; Huang, J.; Teh, B.M.; Hu, S.; Hu, Y.; Shen, Y. Exploration of a predictive model based on genes associated with fatty acid metabolism and clinical treatment for head and neck squamous cell carcinoma. J. Clin. Lab. Anal., 2022, 36(11), e24722.
[http://dx.doi.org/10.1002/jcla.24722] [PMID: 36181275]
[4]
Zhang, X.M.; Song, L.J.; Shen, J.; Yue, H.; Han, Y.Q.; Yang, C.L.; Liu, S.Y.; Deng, J.W.; Jiang, Y.; Fu, G.H.; Shen, W.W. Prognostic and predictive values of immune infiltrate in patients with head and neck squamous cell carcinoma. Hum. Pathol., 2018, 82, 104-112.
[http://dx.doi.org/10.1016/j.humpath.2018.07.012] [PMID: 30036594]
[5]
Muzaffar, J.; Bari, S.; Kirtane, K.; Chung, C.H. Recent advances and future directions in clinical management of head and neck squamous cell carcinoma. Cancers (Basel), 2021, 13(2), 338.
[http://dx.doi.org/10.3390/cancers13020338] [PMID: 33477635]
[6]
Huang, J.; Xu, Z.; Yuan, Z.; Cheng, L.; Zhou, C.; Shen, Y. Identification of cuproptosis‐related subtypes and characterization of the tumor microenvironment landscape in head and neck squamous cell carcinoma. J. Clin. Lab. Anal., 2022, 36(9), e24638.
[http://dx.doi.org/10.1002/jcla.24638] [PMID: 36082469]
[7]
Chen, D.S.; Mellman, I. Elements of cancer immunity and the cancer–immune set point. Nature, 2017, 541(7637), 321-330.
[http://dx.doi.org/10.1038/nature21349] [PMID: 28102259]
[8]
Seiwert, T.Y.; Burtness, B.; Mehra, R.; Weiss, J.; Berger, R.; Eder, J.P.; Heath, K.; McClanahan, T.; Lunceford, J.; Gause, C.; Cheng, J.D.; Chow, L.Q. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol., 2016, 17(7), 956-965.
[http://dx.doi.org/10.1016/S1470-2045(16)30066-3] [PMID: 27247226]
[9]
Samra, B.; Tam, E.; Baseri, B.; Shapira, I. Checkpoint inhibitors in head and neck cancer: current knowledge and perspectives. J. Investig. Med., 2018, 66(7), 1023-1030.
[http://dx.doi.org/10.1136/jim-2018-000743] [PMID: 29941547]
[10]
Huang, J.; Xu, Z.; Teh, B.M.; Zhou, C.; Yuan, Z.; Shi, Y.; Shen, Y. Construction of a necroptosis‐related lncRNA signature to predict the prognosis and immune microenvironment of head and neck squamous cell carcinoma. J. Clin. Lab. Anal., 2022, 36(6), e24480.
[http://dx.doi.org/10.1002/jcla.24480] [PMID: 35522142 ]
[11]
Ferris, R.L.; Whiteside, T.L.; Ferrone, S. Immune escape associated with functional defects in antigen-processing machinery in head and neck cancer. Clin. Cancer Res., 2006, 12(13), 3890-3895.
[http://dx.doi.org/10.1158/1078-0432.CCR-05-2750] [PMID: 16818683]
[12]
Liu, K.; Ma, J.; Ao, J.; Mu, L.; Wang, Y.; Qian, Y.; Xue, J.; Zhang, W. The oncogenic role and immune infiltration for CARM1 identified by pancancer analysis. J. Oncol., 2021, 2021, 1-15.
[http://dx.doi.org/10.1155/2021/2986444] [PMID: 34745258]
[13]
Lu, J.; Xu, J.; Li, J.; Pan, T.; Bai, J.; Wang, L.; Jin, X.; Lin, X.; Zhang, Y.; Li, Y.; Sahni, N.; Li, X. FACER: Comprehensive molecular and functional characterization of epigenetic chromatin regulators. Nucleic Acids Res., 2018, 46(19), 10019-10033.
[http://dx.doi.org/10.1093/nar/gky679] [PMID: 30102398]
[14]
Plass, C.; Pfister, S.M.; Lindroth, A.M.; Bogatyrova, O.; Claus, R.; Lichter, P. Mutations in regulators of the epigenome and their connections to global chromatin patterns in cancer. Nat. Rev. Genet., 2013, 14(11), 765-780.
[http://dx.doi.org/10.1038/nrg3554] [PMID: 24105274]
[15]
Damaschke, N.A.; Yang, B.; Blute, M.L., Jr; Lin, C.P.; Huang, W.; Jarrard, D.F. Frequent disruption of chromodomain helicase DNA-binding protein 8 (CHD8) and functionally associated chromatin regulators in prostate cancer. Neoplasia, 2014, 16(12), 1018-1027.
[http://dx.doi.org/10.1016/j.neo.2014.10.003] [PMID: 25499215]
[16]
Guo, T.; Zambo, K.D.A.; Zamuner, F.T.; Ou, T.; Hopkins, C.; Kelley, D.Z.; Wulf, H.A.; Winkler, E.; Erbe, R.; Danilova, L.; Considine, M.; Sidransky, D.; Favorov, A.; Florea, L.; Fertig, E.J.; Gaykalova, D.A. Chromatin structure regulates cancer-specific alternative splicing events in primary HPV-related oropharyngeal squamous cell carcinoma. Epigenetics, 2020, 15(9), 959-971.
[http://dx.doi.org/10.1080/15592294.2020.1741757] [PMID: 32164487]
[17]
Cao, J.; Yan, Q. Cancer epigenetics, tumor immunity, and immunotherapy. Trends Cancer, 2020, 6(7), 580-592.
[http://dx.doi.org/10.1016/j.trecan.2020.02.003] [PMID: 32610068]
[18]
Haft, S.; Ren, S.; Xu, G.; Mark, A.; Fisch, K.; Guo, T.W.; Khan, Z.; Pang, J.; Ando, M.; Liu, C.; Sakai, A.; Fukusumi, T.; Califano, J.A. Mutation of chromatin regulators and focal hotspot alterations characterize human papillomavirus–positive oropharyngeal squamous cell carcinoma. Cancer, 2019, 125(14), 2423-2434.
[http://dx.doi.org/10.1002/cncr.32068] [PMID: 30933315]
[19]
Geeleher, P.; Cox, N.J.; Huang, R.S. Clinical drug response can be predicted using baseline gene expression levels and in vitro drug sensitivity in cell lines. Genome Biol., 2014, 15(3), R47.
[http://dx.doi.org/10.1186/gb-2014-15-3-r47] [PMID: 24580837]
[20]
Majumder, M.; House, R.; Palanisamy, N.; Qie, S.; Day, T.A.; Neskey, D.; Diehl, J.A.; Palanisamy, V. RNA-Binding Protein FXR1 Regulates p21 and TERC RNA to Bypass p53-Mediated Cellular Senescence in OSCC. PLoS Genet., 2016, 12(9), e1006306.
[http://dx.doi.org/10.1371/journal.pgen.1006306] [PMID: 27606879]
[21]
Fernández, E.; Mallette, F.A. The Rise of FXR1: Escaping cellular senescence in head and neck squamous cell carcinoma. PLoS Genet., 2016, 12(11), e1006344.
[http://dx.doi.org/10.1371/journal.pgen.1006344] [PMID: 27812105]
[22]
Qie, S.; Majumder, M.; Mackiewicz, K.; Howley, B.V.; Peterson, Y.K.; Howe, P.H.; Palanisamy, V.; Diehl, J.A. Fbxo4-mediated degradation of Fxr1 suppresses tumorigenesis in head and neck squamous cell carcinoma. Nat. Commun., 2017, 8(1), 1534.
[http://dx.doi.org/10.1038/s41467-017-01199-8] [PMID: 29142209]
[23]
Jia, L.; Wang, T.; Ding, G.; Kuai, X.; Wang, X.; Wang, B.; Zhao, W.; Zhao, Y. Trop2 inhibition of P16 expression and the cell cycle promotes intracellular calcium release in OSCC. Int. J. Biol. Macromol., 2020, 164, 2409-2417.
[http://dx.doi.org/10.1016/j.ijbiomac.2020.07.234] [PMID: 32768481]
[24]
Luo, K.; Li, Y.; Yin, Y.; Li, L.; Wu, C.; Chen, Y.; Nowsheen, S.; Hu, Q.; Zhang, L.; Lou, Z.; Yuan, J. USP49 negatively regulates tumorigenesis and chemoresistance through FKBP51‐AKT signaling. EMBO J., 2017, 36(10), 1434-1446.
[http://dx.doi.org/10.15252/embj.201695669] [PMID: 28363942]
[25]
Santos, C.R.; Rodríguez-Pinilla, M.; Vega, F.M.; Rodríguez-Peralto, J.L.; Blanco, S.; Sevilla, A.; Valbuena, A.; Hernández, T.; van Wijnen, A.J.; Li, F.; de Alava, E.; Sánchez-Céspedes, M.; Lazo, P.A. VRK1 signaling pathway in the context of the proliferation phenotype in head and neck squamous cell carcinoma. Mol. Cancer Res., 2006, 4(3), 177-185.
[http://dx.doi.org/10.1158/1541-7786.MCR-05-0212] [PMID: 16547155]
[26]
Sethi, S.; Benninger, M.S.; Lu, M.; Havard, S.; Worsham, M.J. Noninvasive molecular detection of head and neck squamous cell carcinoma: an exploratory analysis. Diagn. Mol. Pathol., 2009, 18(2), 81-87.
[http://dx.doi.org/10.1097/PDM.0b013e3181804b82] [PMID: 19430297]
[27]
Wang, J.; Li, J.; Zhang, L.; Qin, Y.; Zhang, F.; Hu, R.; Chen, H.; Tian, Y.; Liu, Z.; Tian, Y.; Zhang, X. Comprehensive analysis of ubiquitin-proteasome system genes related to prognosis and immunosuppression in head and neck squamous cell carcinoma. Aging (Albany NY), 2021, 13(16), 20277-20301.
[http://dx.doi.org/10.18632/aging.203411] [PMID: 34398824]
[28]
Wu, F.; Du, Y.; Hou, X.; Cheng, W. A prognostic model for oral squamous cell carcinoma using 7 genes related to tumor mutational burden. BMC Oral Health, 2022, 22(1), 152.
[http://dx.doi.org/10.1186/s12903-022-02193-3] [PMID: 35488327]
[29]
Shaikh, I.; Ansari, A.; Ayachit, G.; Gandhi, M.; Sharma, P.; Bhairappanavar, S.; Joshi, C.G.; Das, J. Differential gene expression analysis of HNSCC tumors deciphered tobacco dependent and independent molecular signatures. Oncotarget, 2019, 10(58), 6168-6183.
[http://dx.doi.org/10.18632/oncotarget.27249] [PMID: 31692905]
[30]
Duan, Q.; Zhang, H.; Zheng, J.; Zhang, L. Turning cold into hot: Firing up the tumor microenvironment. Trends Cancer, 2020, 6(7), 605-618.
[http://dx.doi.org/10.1016/j.trecan.2020.02.022] [PMID: 32610070]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy