Prognostic Value of Iroquois Homeobox 1 Methylation in Non-small Cell Lung Cancers

Overview

Journal Genes Genomics

Specialty Genetics

Date 2020 Mar 23

PMID 32200543

Citations 5

Authors

Ji Yun Lee

Won Kee Lee

Jae Yong Park

Dong Sun Kim

Affiliations

Soon will be listed here.

Abstract

Background: Non-small cell lung cancer (NSCLC) poses a great threat to human health. DNA methylation abnormalities play a central role in the development and outcome of most human malignancies, providing potential biomarkers for diagnosis and prognosis. Iroquois homeobox 1 (IRX1) can act as a tumor suppressor or promoter depending on the tumor microenvironment, and its role in lung cancer is still controversial.

Objective: The purpose of this study was to investigate the biological role and prognostic value of IRX1 in NSCLC.

Methods: We examined the methylation status of IRX1 promoter in 146 tumors from patients with NSCLC using pyrosequencing and analyzed the association between methylation status and overall patient survival.

Results: A total of 37 cases (25.3%) showed IRX1 methylation-positive tumors when compared with matched normal tissues. No association between IRX1 expression level and methylation status was found in lung cancer cell lines. IRX1 methylation significantly correlated with smoking status and TP53 mutation. Patients with IRX1 methylation showed significantly longer survival than patients without methylation (log-rank P = 0.011). In a multivariate analysis of prognostic factors, IRX1 methylation in tumor samples was an independent prognostic factor (adjusted hazard ratio = 0.35, 95% confidence interval 0.17-0.73, P = 0.005).

Conclusion: These results suggest that IRX1 promoter methylation may be a tumor-associated event and an independent predictor of survival advantage in patients with NSCLC. Further large-scale studies are needed to confirm these findings.

Citing Articles

Genetic and functional analysis of Raynaud's syndrome implicates loci in vasculature and immunity.

Tervi A, Ramste M, Abner E, Cheng P, Lane J, Maher M Cell Genom. 2024; 4(9):100630.

PMID: 39142284 PMC: 11480858. DOI: 10.1016/j.xgen.2024.100630.

Iroquois Family Genes in Gastric Carcinogenesis: A Comprehensive Review.

Dos Santos E, Petrone I, Binato R, Abdelhay E Genes (Basel). 2023; 14(3).

PMID: 36980893 PMC: 10048635. DOI: 10.3390/genes14030621.

Differential DNA methylation and mRNA transcription in gingival tissues in periodontal health and disease.

Kim H, Momen-Heravi F, Chen S, Hoffmann P, Kebschull M, Papapanou P J Clin Periodontol. 2021; 48(9):1152-1164.

PMID: 34101221 PMC: 8376779. DOI: 10.1111/jcpe.13504.

Epigenetic Inactivation of the Tumor Suppressor Occurs Frequently in Lung Adenocarcinoma and Its Silencing Is Associated with Impaired Prognosis.

Kuster M, Schneider M, Richter A, Richtmann S, Winter H, Kriegsmann M Cancers (Basel). 2020; 12(12).

PMID: 33256112 PMC: 7760495. DOI: 10.3390/cancers12123528.

Combined Methylome and Transcriptome Analyses Reveals Potential Therapeutic Targets for EGFR Wild Type Lung Cancers with Low PD-L1 Expression.

Hu W, Wang G, Yarmus L, Wan Y Cancers (Basel). 2020; 12(9).

PMID: 32899191 PMC: 7563876. DOI: 10.3390/cancers12092496.

References

Seok Y, Lee W, Park J, Kim D . Promoter Methylation is Associated with Poor Prognosis in Lung Adenocarcinoma Patients. Mol Cells. 2019; 42(2):161-165. PMC: 6399005. DOI: 10.14348/molcells.2018.0322. View

Lessi F, Beggs A, de Palo M, Anti M, Palmieri R, Francesconi S . Down-regulation of serum/glucocorticoid regulated kinase 1 in colorectal tumours is largely independent of promoter hypermethylation. PLoS One. 2010; 5(11):e13840. PMC: 2974649. DOI: 10.1371/journal.pone.0013840. View

Lu F, Zhang H . DNA methylation and nonsmall cell lung cancer. Anat Rec (Hoboken). 2011; 294(11):1787-95. DOI: 10.1002/ar.21471. View

Marcinkiewicz K, Gudas L . Altered histone mark deposition and DNA methylation at homeobox genes in human oral squamous cell carcinoma. J Cell Physiol. 2014; 229(10):1405-16. PMC: 4206563. DOI: 10.1002/jcp.24577. View

Spiro S, Silvestri G . One hundred years of lung cancer. Am J Respir Crit Care Med. 2005; 172(5):523-9. DOI: 10.1164/rccm.200504-531OE. View

Tan Q, Wang G, Huang J, Ding Z, Luo Q, Mok T . Epigenomic analysis of lung adenocarcinoma reveals novel DNA methylation patterns associated with smoking. Onco Targets Ther. 2013; 6:1471-9. PMC: 3818101. DOI: 10.2147/OTT.S51041. View

Gao C, Zhuang J, Zhou C, Ma K, Zhao M, Liu C . Prognostic value of aberrantly expressed methylation gene profiles in lung squamous cell carcinoma: A study based on The Cancer Genome Atlas. J Cell Physiol. 2018; 234(5):6519-6528. DOI: 10.1002/jcp.27389. View

Selamat S, Chung B, Girard L, Zhang W, Zhang Y, Campan M . Genome-scale analysis of DNA methylation in lung adenocarcinoma and integration with mRNA expression. Genome Res. 2012; 22(7):1197-211. PMC: 3396362. DOI: 10.1101/gr.132662.111. View

Zhang P, Liu N, Xu X, Wang Z, Cheng Y, Jin W . Clinical significance of Iroquois Homeobox Gene - IRX1 in human glioma. Mol Med Rep. 2018; 17(3):4651-4656. DOI: 10.3892/mmr.2018.8404. View

10.

Yu W, Li X, Eliason S, Romero-Bustillos M, Ries R, Cao H . Irx1 regulates dental outer enamel epithelial and lung alveolar type II epithelial differentiation. Dev Biol. 2017; 429(1):44-55. PMC: 5599132. DOI: 10.1016/j.ydbio.2017.07.011. View

11.

Jankowska A, Millward C, Caldwell C . The potential of DNA modifications as biomarkers and therapeutic targets in oncology. Expert Rev Mol Diagn. 2015; 15(10):1325-37. DOI: 10.1586/14737159.2015.1084229. View

12.

Kim D, Lee W, Park J . Hypermethylation of normal mucosa of esophagus-specific 1 is associated with an unfavorable prognosis in patients with non-small cell lung cancer. Oncol Lett. 2018; 16(2):2409-2415. PMC: 6036558. DOI: 10.3892/ol.2018.8915. View

13.

Doi T, Lukosiute A, Ruttenstock E, Dingemann J, Puri P . Expression of Iroquois genes is up-regulated during early lung development in the nitrofen-induced pulmonary hypoplasia. J Pediatr Surg. 2011; 46(1):62-6. DOI: 10.1016/j.jpedsurg.2010.09.059. View

14.

Mahoney S, Yao Z, Keyes C, Tapscott S, Diede S . Genome-wide DNA methylation studies suggest distinct DNA methylation patterns in pediatric embryonal and alveolar rhabdomyosarcomas. Epigenetics. 2012; 7(4):400-8. PMC: 3368822. DOI: 10.4161/epi.19463. View

15.

Zhou C, Ye M, Ni S, Li Q, Ye D, Li J . DNA methylation biomarkers for head and neck squamous cell carcinoma. Epigenetics. 2018; 13(4):398-409. PMC: 6140809. DOI: 10.1080/15592294.2018.1465790. View

16.

Kuhn A, Loscher D, Marschalek R . The IRX1/HOXA connection: insights into a novel t(4;11)- specific cancer mechanism. Oncotarget. 2016; 7(23):35341-52. PMC: 5085233. DOI: 10.18632/oncotarget.9241. View

17.

Bennett K, Lee W, Lamarre E, Zhang X, Seth R, Scharpf J . HPV status-independent association of alcohol and tobacco exposure or prior radiation therapy with promoter methylation of FUSSEL18, EBF3, IRX1, and SEPT9, but not SLC5A8, in head and neck squamous cell carcinomas. Genes Chromosomes Cancer. 2009; 49(4):319-26. DOI: 10.1002/gcc.20742. View

18.

Lu J, Song G, Tang Q, Zou C, Han F, Zhao Z . IRX1 hypomethylation promotes osteosarcoma metastasis via induction of CXCL14/NF-κB signaling. J Clin Invest. 2015; 125(5):1839-56. PMC: 4463198. DOI: 10.1172/JCI78437. View

19.

Bennett K, Karpenko M, Lin M, Claus R, Arab K, Dyckhoff G . Frequently methylated tumor suppressor genes in head and neck squamous cell carcinoma. Cancer Res. 2008; 68(12):4494-9. DOI: 10.1158/0008-5472.CAN-07-6509. View

20.

Chen C, Yin N, Yin B, Lu Q . DNA methylation in thoracic neoplasms. Cancer Lett. 2010; 301(1):7-16. DOI: 10.1016/j.canlet.2010.10.017. View