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Combinatorial Chemistry & High Throughput Screening

Editor-in-Chief

ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

Research Article

A Novel Tumor Mutation Burden Related lncRNA Signature Identified Prognosis and Tumor Immune Microenvironment Features in Clear Cell Renal Cell Carcinoma

Author(s): Lin Lin, Xiao-Hui Wu, Jun-Ming Zhu, Shao-Hao Chen, Ye-Hui Chen, Fei Lin, Xue-Yi Xue, Yong Wei, Ning Xu, Qing-Shui Zheng* and Xiong-Lin Sun*

Volume 26, Issue 8, 2023

Published on: 31 October, 2022

Page: [1503 - 1518] Pages: 16

DOI: 10.2174/1386207325666220926123923

open access plus

Abstract

Background: Emerging evidence indicates that long noncoding RNA (lncRNA) plays an important biological role in clear cell renal cell carcinoma (ccRCC); however, the clinical value of tumor mutation burden-related lncRNA in ccRCC patients is unknown yet.

Methods: Somatic mutation profiles and lncRNA expression data of ccRCC were downloaded from the TCGA database. We retrospectively analyzed lncRNA expression data and survival information from 116 patients with ccRCC fromJanuary 2013 to January 2014. Univariate and multivariate Cox regression analyses were performed to construct lncRNA signature, and the prognosis value was determined by Kaplan-Mayer and receiver operating characteristic curve (ROC) analysis.

Results: Based on 160 differentially expressed TMB-related lncRNAs, two TMB-related molecular clusters with distinct immune checkpoints expression and immune cells infiltration were established for ccRCC patients. Moreover, a novel TMB-related lncRNA signature was constructed based on five lncRNAs for individualized prognosis assessment. High-risk group represents significantly worse overall survival in all cohorts. The area under the ROC curve was 0.716, 0.775 and 0.744 in the training cohort, testing cohort and TCGA cohort, respectively. Results of qRT-PCR successfully validated the expression levels of AP002360.3, LINC00460, AL590094.1, LINC00944 and LINC01843 in HK-2, 786-O, 769-P and ACHN cells. More importantly, the predictive performance of TMB-related lncRNA signature was successfully validated in an independent cohort of 116 ccRCC patients at our institution.

Conclusion: This study successfully developed and validated a novel TMB-related lncRNA signature for individualized prognosis assessment of ccRCC patients.

Keywords: Clear cell renal cell carcinoma, long non-coding RNA, tumor mutation burden, prognostic model, tumor immune microenvironment, immune cells.

Graphical Abstract
[1]
Capitanio, U.; Montorsi, F. Renal cancer. Lancet, 2016, 387(10021), 894-906.
[http://dx.doi.org/10.1016/S0140-6736(15)00046-X] [PMID: 26318520]
[2]
Ljungberg, B.; Bensalah, K.; Canfield, S.; Dabestani, S.; Hofmann, F.; Hora, M.; Kuczyk, M.A.; Lam, T.; Marconi, L.; Merseburger, A.S.; Mulders, P.; Powles, T.; Staehler, M.; Volpe, A.; Bex, A. EAU guidelines on renal cell carcinoma: 2014 update. Eur. Urol., 2015, 67(5), 913-924.
[http://dx.doi.org/10.1016/j.eururo.2015.01.005] [PMID: 25616710]
[3]
Dalbeni, A.; Ciccarese, C.; Bevilacqua, M.; Benati, M.; Caimmi, C.; Cerrito, L.; Famà, F.; Iacovelli, R.; Mantovani, A.; Meneguzzi, F.; Minuz, P.; Montagnana, M.; Orsolini, G.; Rossini, M.; Tortora, G.; Viapiana, O.; Fava, C. Effects of antiangiogenetic drugs on microcirculation and macrocirculation in patients with advanced-stage renal cancer. Cancers, 2018, 11(1), 30.
[http://dx.doi.org/10.3390/cancers11010030] [PMID: 30597890]
[4]
Van Poppel, H.; Becker, F.; Cadeddu, J.A.; Gill, I.S.; Janetschek, G.; Jewett, M.A.S.; Laguna, M.P.; Marberger, M.; Montorsi, F.; Polascik, T.J.; Ukimura, O.; Zhu, G. Treatment of localised renal cell carcinoma. Eur. Urol., 2011, 60(4), 662-672.
[http://dx.doi.org/10.1016/j.eururo.2011.06.040] [PMID: 21726933]
[5]
Rini, B.I.; Battle, D.; Figlin, R.A.; George, D.J.; Hammers, H.; Hutson, T.; Jonasch, E.; Joseph, R.W.; McDermott, D.F.; Motzer, R.J.; Pal, S.K.; Pantuck, A.J.; Quinn, D.I.; Seery, V.; Voss, M.H.; Wood, C.G.; Wood, L.S.; Atkins, M.B. The society for immunotherapy of cancer consensus statement on immunotherapy for the treatment of advanced Renal Cell Carcinoma (RCC). J. Immunother. Cancer, 2019, 7(1), 354.
[http://dx.doi.org/10.1186/s40425-019-0813-8] [PMID: 31856918]
[6]
Chalmers, Z.R.; Connelly, C.F.; Fabrizio, D.; Gay, L.; Ali, S.M.; Ennis, R.; Schrock, A.; Campbell, B.; Shlien, A.; Chmielecki, J.; Huang, F.; He, Y.; Sun, J.; Tabori, U.; Kennedy, M.; Lieber, D.S.; Roels, S.; White, J.; Otto, G.A.; Ross, J.S.; Garraway, L.; Miller, V.A.; Stephens, P.J.; Frampton, G.M. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med., 2017, 9(1), 34.
[http://dx.doi.org/10.1186/s13073-017-0424-2] [PMID: 28420421]
[7]
Chan, T.A.; Yarchoan, M.; Jaffee, E.; Swanton, C.; Quezada, S.A.; Stenzinger, A.; Peters, S. Development of tumor mutation burden as an immunotherapy biomarker: Utility for the oncology clinic. Ann. Oncol., 2019, 30(1), 44-56.
[http://dx.doi.org/10.1093/annonc/mdy495] [PMID: 30395155]
[8]
Lu, N.; Liu, J.; Ji, C.; Wang, Y.; Wu, Z.; Yuan, S.; Xing, Y.; Diao, F. MiRNA based tumor mutation burden diagnostic and prognostic prediction models for endometrial cancer. Bioengineered, 2021, 12(1), 3603-3620.
[http://dx.doi.org/10.1080/21655979.2021.1947940] [PMID: 34252354]
[9]
Zhang, S.; Chen, S.; Wang, Y.; Zhan, Y.; Li, J.; Nong, X.; Gao, B. Association of a novel prognosis model with tumor mutation burden and tumor-infiltrating immune cells in thyroid carcinoma. Front. Genet., 2021, 12, 744304.
[http://dx.doi.org/10.3389/fgene.2021.744304] [PMID: 34976004]
[10]
Kang, K.; Xie, F.; Mao, J.; Bai, Y.; Wang, X. Significance of tumor mutation burden in immune infiltration and prognosis in cutaneous melanoma. Front. Oncol., 2020, 10, 573141.
[http://dx.doi.org/10.3389/fonc.2020.573141] [PMID: 33072607]
[11]
Yan, B.; Wang, Z.H.; Guo, J.T. The research strategies for probing the function of long noncoding RNAs. Genomics, 2012, 99(2), 76-80.
[http://dx.doi.org/10.1016/j.ygeno.2011.12.002] [PMID: 22210346]
[12]
Huarte, M. The emerging role of lncRNAs in cancer. Nat. Med., 2015, 21(11), 1253-1261.
[http://dx.doi.org/10.1038/nm.3981] [PMID: 26540387]
[13]
Yoshihara, K.; Shahmoradgoli, M.; Martínez, E.; Vegesna, R.; Kim, H.; Torres, G.W.; Treviño, V.; Shen, H.; Laird, P.W.; Levine, D.A.; Carter, S.L.; Getz, G.; Stemke-Hale, K.; Mills, G.B.; Verhaak, R.G.W. Inferring tumour purity and stromal and immune cell admixture from expression data. Nat. Commun., 2013, 4(1), 2612.
[http://dx.doi.org/10.1038/ncomms3612] [PMID: 24113773]
[14]
Ke, Z.B.; Wu, Y.P.; Huang, P.; Hou, J.; Chen, Y.H.; Dong, R.N.; Lin, F.; Wei, Y.; Xue, X.Y.; Ng, C.F.; Xu, N. Identification of novel genes in testicular cancer microenvironment based on estimate algorithm‐derived immune scores. J. Cell. Physiol., 2021, 236(1), 706-713.
[http://dx.doi.org/10.1002/jcp.29898] [PMID: 32617980]
[15]
Newman, A.M.; Liu, C.L.; Green, M.R.; Gentles, A.J.; Feng, W.; Xu, Y.; Hoang, C.D.; Diehn, M.; Alizadeh, A.A. Robust enumeration of cell subsets from tissue expression profiles. Nat. Methods, 2015, 12(5), 453-457.
[http://dx.doi.org/10.1038/nmeth.3337] [PMID: 25822800]
[16]
Miao, D.; Margolis, C.A.; Gao, W.; Voss, M.H.; Li, W.; Martini, D.J.; Norton, C.; Bossé, D.; Wankowicz, S.M.; Cullen, D.; Horak, C.; Wind, R.M.; Tracy, A.; Giannakis, M.; Hodi, F.S.; Drake, C.G.; Ball, M.W.; Allaf, M.E.; Snyder, A.; Hellmann, M.D.; Ho, T.; Motzer, R.J.; Signoretti, S.; Kaelin, W.G., Jr; Choueiri, T.K.; Van Allen, E.M. Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma. Science, 2018, 359(6377), 801-806.
[http://dx.doi.org/10.1126/science.aan5951] [PMID: 29301960]
[17]
Aran, D.; Hu, Z.; Butte, A.J. xCell: Digitally portraying the tissue cellular heterogeneity landscape. Genome Biol., 2017, 18(1), 220.
[http://dx.doi.org/10.1186/s13059-017-1349-1] [PMID: 29141660]
[18]
Subramanian, A.; Kuehn, H.; Gould, J.; Tamayo, P.; Mesirov, J.P. GSEA-P: A desktop application for gene set enrichment analysis. Bioinformatics, 2007, 23(23), 3251-3253.
[http://dx.doi.org/10.1093/bioinformatics/btm369] [PMID: 17644558]
[19]
Valera, V.A.; Merino, M.J. Misdiagnosis of clear cell renal cell carcinoma. Nat. Rev. Urol., 2011, 8(6), 321-333.
[http://dx.doi.org/10.1038/nrurol.2011.64] [PMID: 21587224]
[20]
Zhai, W.; Zhu, R.; Ma, J.; Gong, D.; Zhang, H.; Zhang, J.; Chen, Y.; Huang, Y.; Zheng, J.; Xue, W. A positive feed-forward loop between LncRNA-URRCC and EGFL7/P-AKT/FOXO3 signaling promotes proliferation and metastasis of clear cell renal cell carcinoma. Mol. Cancer, 2019, 18(1), 81.
[http://dx.doi.org/10.1186/s12943-019-0998-y] [PMID: 30953521]
[21]
Chen, C.; Zheng, H. LncRNA LINC00944 promotes tumorigenesis but suppresses Akt phosphorylation in renal cell carcinoma. Front. Mol. Biosci., 2021, 8, 697962.
[http://dx.doi.org/10.3389/fmolb.2021.697962] [PMID: 34291088]
[22]
Chen, B.; Zhang, K.; Han, Q.; Zhong, W.; Yi, J.; Zhu, H.; Xia, S. LncRNA LINC00460 takes a stimulating role on hepatocellular carcinoma stemness property. Cell Cycle, 2021, 20(20), 2102-2113.
[http://dx.doi.org/10.1080/15384101.2021.1940627] [PMID: 34612153]
[23]
Corrigendum to “Long noncoding RNA LINC00460 promotes cell progression by sponging mir-4443 in head and neck squamous cell carcinoma. Cell Transplant., 2021, 30, 9636897211058137.
[PMID: 34719280]
[24]
Hou, P.; Meng, S.; Li, M.; Lin, T.; Chu, S.; Li, Z.; Zheng, J.; Gu, Y.; Bai, J. Correction to: LINC00460/DHX9/IGF2BP2 complex promotes colorectal cancer proliferation and metastasis by mediating HMGA1 mRNA stability depending on m6A modification. J. Exp. Clin. Cancer Res., 2021, 40(1), 365.
[http://dx.doi.org/10.1186/s13046-021-02169-1] [PMID: 34784937]
[25]
Chen, X.; Song, J.; Wang, X.; Sun, D.; Liu, Y.; Jiang, Y. LNCRNA LINC00460: Function and mechanism in human cancer. Thorac. Cancer, 2022, 13(1), 3-14.
[http://dx.doi.org/10.1111/1759-7714.14238] [PMID: 34821482]
[26]
Zhang, S.; Zhang, F.; Niu, Y.; Yu, S. Aberration of lncRNA LINC00460 is a promising prognosis factor and associated with progression of clear cell renal cell carcinoma. Cancer Manag. Res., 2021, 13, 6489-6497.
[http://dx.doi.org/10.2147/CMAR.S322747] [PMID: 34429655]
[27]
Deleuze, A.; Saout, J.; Dugay, F.; Peyronnet, B.; Mathieu, R.; Verhoest, G.; Bensalah, K.; Crouzet, L.; Laguerre, B.; Belaud, R.M.A.; Rioux, L.N.; Kammerer, J.S.F. Immunotherapy in renal cell carcinoma: The future is now. Int. J. Mol. Sci., 2020, 21(7), 2532.
[http://dx.doi.org/10.3390/ijms21072532] [PMID: 32260578]
[28]
Yang, D.; Yu, J.; Han, B.; Sun, Y.; Mo, S.; Hu, J. Long non-coding RNA expression patterns in stomach adenocarcinoma serve as an indicator of tumor mutation burden and are associated with tumor-infiltrating lymphocytes and microsatellite instability. Front. Cell Dev. Biol., 2021, 9, 618313.
[http://dx.doi.org/10.3389/fcell.2021.618313] [PMID: 33644056]
[29]
Zhang, L.; Li, L.; Zhan, Y.; Wang, J.; Zhu, Z.; Zhang, X. Identification of immune-related lncRNA signature to predict prognosis and immunotherapeutic efficiency in bladder cancer. Front. Oncol., 2021, 10, 542140.
[http://dx.doi.org/10.3389/fonc.2020.542140] [PMID: 33552945]

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