ONCOLOGY / BASIC RESEARCH
 
KEYWORDS
TOPICS
ABSTRACT
Introduction:
This study aimed to explore the potential genetic and epigenetic mechanisms associated with IDO1 mRNA dysregulation in esophageal cancer (ESCA).

Material and methods:
Data from The Cancer Genome Atlas (TCGA)-ESCA and the Genotype-Tissue Expression (GTEx) project were obtained for analysis. Subgroup analysis was performed in esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (ESAD).

Results:
IDO1 mRNA expression was significantly upregulated in ESAD and ESCC tissues compared to normal esophagus. Although gene-level copy number alterations were common in both ESAD and ESCC, they were not associated with IDO1 dysregulation. Among 3 CpG sites (cg10262052 and cg08465774 in promoter and cg24188163 in gene body) in the IDO1 gene locus examined, only cg10262052 was hypomethylated in cancerous tissues compared to normal tissues in ESAD. All 3 sites showed significantly different methylation in ESCC than in normal tissues, among which cg10262052 and cg08465774 were hypomethylated, while cg24188163 was hypomethylated. Correlation analysis confirmed negative correlations between cg10262052/cg08465774 methylation and IDO1 expression, while cg24188163 methylation was positively correlated with IDO1 expression (Pearson’s r = 0.45) in ESCC patients. Genomic study confirmed that cg24188163 is in the flanking region of an intragenic promoter of IDO1. IDO1 expression had an independent prognostic value in terms of overall survival (OS) in ESCC patients (HR = 1.183, 95% CI: 1.025–1.367, p = 0.022), but was not a risk factor of unfavorable OS in ESAD patients.

Conclusions:
IDO1 mRNA upregulation was associated with both promoter hypomethylation and gene body hypermethylation in ESCC. Its expression has a specific prognostic value in terms of OS in ESCC, but not in ESAD patients.
REFERENCES (34)
1.
Zhai L, Ladomersky E, Lenzen A, et al. IDO1 in cancer: a Gemini of immune checkpoints. Cell Mol Immunol 2018; 15: 447-57.
 
2.
Ambrosio LF, Insfran C, Volpini X, et al. Role of aryl hydrocarbon receptor (AhR) in the regulation of immunity and immunopathology during trypanosoma cruzi infection. Front Immunol 2019; 10: 631.
 
3.
Lemos H, Huang L, Prendergast GC, Mellor AL. Immune control by amino acid catabolism during tumorigenesis and therapy. Nat Rev Cancer 2019; 19: 162-75.
 
4.
Conway JR, Kofman E, Mo SS, Elmarakeby H, Van Allen E. Genomics of response to immune checkpoint therapies for cancer: implications for precision medicine. Genome Med 2018; 10: 93.
 
5.
Doi T, Piha-Paul SA, Jalal SI, et al. Safety and antitumor activity of the anti-programmed death-1 antibody pembrolizumab in patients with advanced esophageal carcinoma. J Clin Oncol 2018; 36: 61-7.
 
6.
Botticelli A, Cerbelli B, Lionetto L, et al. Can IDO activity predict primary resistance to anti-PD-1 treatment in NSCLC? J Transl Med 2018; 16: 219.
 
7.
Ladomersky E, Zhai L, Lenzen A, et al. IDO1 inhibition synergizes with radiation and PD-1 blockade to durably increase survival against advanced glioblastoma. Clin Cancer Res 2018; 24: 2559-73.
 
8.
Rosenberg AJ, Wainwright DA, Rademaker A, et al. Indoleamine 2,3-dioxygenase 1 and overall survival of patients diagnosed with esophageal cancer. Oncotarget 2018; 9: 23482-93.
 
9.
Zhou S, Zhao L, Liang Z, et al. Indoleamine 2,3-dioxygenase 1 and programmed cell death-ligand 1 co-expression predicts poor pathologic response and recurrence in esophageal squamous cell carcinoma after neoadjuvant chemoradiotherapy. Cancers (Basel) 2019; 11: 169.
 
10.
Kiyozumi Y, Baba Y, Okadome K, et al. Indoleamine 2, 3-dioxygenase 1 promoter hypomethylation is associated with poor prognosis in patients with esophageal cancer. Cancer Sci 2019; 110: 1863-71.
 
11.
Kiyozumi Y, Baba Y, Okadome K, et al. IDO1 expression is associated with immune tolerance and poor prognosis in patients with surgically resected esophageal cancer. Ann Surg 2019; 269: 1101-8.
 
12.
Dewi DL, Mohapatra SR, Blanco Cabanes S, et al. Suppression of indoleamine-2,3-dioxygenase 1 expression by promoter hypermethylation in ER-positive breast cancer. Oncoimmunology 2017; 6: e1274477.
 
13.
Noonepalle SK, Gu F, Lee EJ, et al. Promoter methylation modulates indoleamine 2,3-dioxygenase 1 induction by activated T cells in human breast cancers. Cancer Immunol Res 2017; 5: 330-44.
 
14.
Bandla S, Pennathur A, Luketich JD, et al. Comparative genomics of esophageal adenocarcinoma and squamous cell carcinoma. Ann Thorac Surg 2012; 93: 1101-6.
 
15.
Salem ME, Puccini A, Xiu J, et al. Comparative molecular analyses of esophageal squamous cell carcinoma, esophageal adenocarcinoma, and gastric adenocarcinoma. Oncologist 2018; 23: 1319-27.
 
16.
Lin DC, Dinh HQ, Xie JJ, et al. Identification of distinct mutational patterns and new driver genes in oesophageal squamous cell carcinomas and adenocarcinomas. Gut 2018; 67: 1769-79.
 
17.
Ma W, Zhang CQ, Dang CX, et al. Upregulated long-non-coding RNA DLEU2 exon 9 expression was an independent indicator of unfavorable overall survival in patients with esophageal adenocarcinoma. Biomed Pharmacother 2019; 113: 108655.
 
18.
Mermel CH, Schumacher SE, Hill B, Meyerson ML, Beroukhim R, Getz G. GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol 2011; 12: R41.
 
19.
Goldman M, Craft B, Kamath A, Brooks AN, Zhu J, Haussler D. The UCSC Xena Platform for cancer genomics data visualization and interpretation. bioRxiv 2018: 326470.
 
20.
GTEx Consortium. Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science 2015; 348: 648-60.
 
21.
GTEx Consortium. The Genotype-Tissue Expression (GTEx) project. Nat Genet 2013; 45: 580-5.
 
22.
Hunt SE, McLaren W, Gil L, et al. Ensembl variation resources. Database (Oxford) 2018; 2018: 119.
 
23.
Zhu X, Luo X, Feng G, et al. CENPE expression is associated with its DNA methylation status in esophageal adenocarcinoma and independently predicts unfavorable overall survival. PLoS One 2019; 14: e0207341.
 
24.
Uhlen M, Oksvold P, Fagerberg L, et al. Towards a knowledge-based Human Protein Atlas. Nat Biotechnol 2010; 28: 1248-50.
 
25.
Yasui H, Takai K, Yoshida R, Hayaishi O. Interferon enhances tryptophan metabolism by inducing pulmonary indoleamine 2,3-dioxygenase: its possible occurrence in cancer patients. Proc Natl Acad Sci USA 1986; 83: 6622-6.
 
26.
Vogel CF, Goth SR, Dong B, Pessah IN, Matsumura F. Aryl hydrocarbon receptor signaling mediates expression of indoleamine 2,3-dioxygenase. Biochem Biophys Res Commun 2008; 375: 331-5.
 
27.
Nguyen NT, Kimura A, Nakahama T, et al. Aryl hydrocarbon receptor negatively regulates dendritic cell immunogenicity via a kynurenine-dependent mechanism. Proc Natl Acad Sci USA 2010; 107: 19961-6.
 
28.
Yang X, Han H, De Carvalho DD, Lay FD, Jones PA, Liang G. Gene body methylation can alter gene expression and is a therapeutic target in cancer. Cancer Cell 2014; 26: 577-90.
 
29.
Maunakea AK, Nagarajan RP, Bilenky M, et al. Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature 2010; 466: 253-7.
 
30.
Luco RF, Allo M, Schor IE, Kornblihtt AR, Misteli T. Epigenetics in alternative pre-mRNA splicing. Cell 2011; 144: 16-26.
 
31.
Shukla S, Kavak E, Gregory M, et al. CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing. Nature 2011; 479: 74-9.
 
32.
Marina RJ, Sturgill D, Bailly MA, et al. TET-catalyzed oxidation of intragenic 5-methylcytosine regulates CTCF-dependent alternative splicing. EMBO J 2016; 35: 335-55.
 
33.
Ehrlich M, Ehrlich KC. DNA cytosine methylation and hydroxymethylation at the borders. Epigenomics 2014; 6: 563-6.
 
34.
Carvalho AT, Gouveia L, Kanna CR, Warmlander SK, Platts JA, Kamerlin SC. Understanding the structural and dynamic consequences of DNA epigenetic modifications: computational insights into cytosine methylation and hydroxymethylation. Epigenetics 2014; 9: 1604-12.
 
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ISSN:1734-1922
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