Expression and clinical significance of <i>H2AFX</i> gene in lung adenocarcinoma_West China Medical Journal

Authors：

 CAO Lingjie , GUO Yujie , LI Peiquan , ZHEN Yan , WANG Runyang , WEI Jiaqing

The Second Clinical Medical College, Shanxi Medical University, Taiyuan, Shanxi 030000, P. R. China;

Corresponding author：

CAO Lingjie, Email: cao0604@126.com

Keywords：

Lung adenocarcinoma; H2AFX gene; The Cancer Genome Atlas

DOI：

10.7507/1002-0179.202008178

Video：

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Objective To analyze the expression of H2A histone family, member X (H2AFX) gene in lung adenocarcinoma and its influence on prognosis. Methods We analyzed the expression level of H2AFX gene in the tumor tissues (497 cases) and normal adjacent tissues (54 cases) of lung adenocarcinoma patients via The Cancer Genome Atlas. The patients were divided into high expression group and low expression group according to the expression level of H2AFX gene in lung adenocarcinoma samples. The relationship between H2AFX and clinicopathological features of patients was analyzed through logistic regression. Kaplan-Meier survival curve and log-rank test were used to study the correlation between H2AFX expression and the prognosis of lung adenocarcinoma patients. Univariate and multiple Cox regression analyses were performed to determine the prognostic significance of H2AFX expression in lung adenocarcinoma patients. The research also covered H2AFX-related pathways of genes in the development of lung adenocarcinoma with gene set enrichment analysis (GSEA). Results The H2AFX expression was higher in lung adenocarcinoma tissues than that in normal adjacent tissues (P<0.001). Besides, it was significantly correlated with age (P<0.001), T staging (P=0.007), and N staging (P=0.010), but had little to do with M staging or gender (P>0.05). Kaplan-Meier survival curve and log-rank test showed that the survival rate of patients with high H2AFX expression was vastly lower than that of patients with low H2AFX expression (P<0.001). Multiple Cox regression analysis demonstrated that H2AFX could be an independent prognostic factor for lung adenocarcinoma [hazard ratio=1.41, 95% confidence interval (1.11, 1.78), P=0.004]. The results of GSEA displayed that H2AFX was involved in cell cycle, homologous recombination, DNA replication, base excision and repair, spliceosome, mismatch repair, p53 signaling pathway, nucleotide excision and repair, RNA degradation, RNA polymerase, and other pathways. Conclusions The expression of H2AFX gene is high in lung adenocarcinoma, and closely connected to the prognosis, occurrence, and evolution of lung adenocarcinoma. This gene can be one of the new molecular markers and therapeutic targets for lung adenocarcinoma.

Citation： CAO Lingjie, GUO Yujie, LI Peiquan, ZHEN Yan, WANG Runyang, WEI Jiaqing. Expression and clinical significance of H2AFX gene in lung adenocarcinoma. West China Medical Journal, 2022, 37(2): 224-230. doi: 10.7507/1002-0179.202008178 Copy

1.	Guo T, Zhao S, Wang P, et al. YB-1 regulates tumor growth by promoting MACC1/c-Met pathway in human lung adenocarcinoma. Oncotarget, 2017, 8(29): 48110-48125.
2.	Wei X, Zhang K, Qin H, et al. GMDS knockdown impairs cell proliferation and survival in human lung adenocarcinoma. BMC Cancer, 2018, 18(1): 600.
3.	Ferrer I, Quintanal-Villalonga Á, Molina-Pinelo S, et al. MAP17 predicts sensitivity to platinum-based therapy, EGFR inhibitors and the proteasome inhibitor bortezomib in lung adenocarcinoma. J Exp Clin Cancer Res, 2018, 37(1): 195.
4.	Liao M, Liu Q, Li B, et al. A group of long noncoding RNAs identified by data mining can predict the prognosis of lung adenocarcinoma. Cancer Sci, 2018, 109(12): 4033-4044.
5.	Zhang Y, Sun L, Gao X, et al. RNF43 ubiquitinates and degrades phosphorylated E-cadherin by c-Src to facilitate epithelial-mesenchymal transition in lung adenocarcinoma. BMC Cancer, 2019, 19(1): 670.
6.	He SY, Xi WJ, Wang X, et al. Identification of a combined RNA prognostic signature in adenocarcinoma of the lung. Med Sci Monit, 2019, 25: 3941-3956.
7.	Ding F, Wang D, Li XK, et al. Overexpression of S100A14 contributes to malignant progression and predicts poor prognosis of lung adenocarcinoma. Thorac Cancer, 2018, 9(7): 827-835.
8.	Lu JC, Wei QY, Bondy ML, et al. Genetic variants in the H2AFX promoter region are associated with risk of sporadic breast cancer in non-Hispanic white women aged ≤55 years. Breast Cancer Res Treat, 2008, 110(2): 357-366.
9.	Podralska M, Ziółkowska-Suchanek I, Żurawek M, et al. Genetic variants in ATM, H2AFX and MRE11 genes and susceptibility to breast cancer in the Polish population. BMC Cancer, 2018, 18(1): 452.
10.	Srivastava N, Manvati S, Srivastava A, et al. miR-24-2 controls H2AFX expression regardless of gene copy number alteration and induces apoptosis by targeting antiapoptotic gene BCL-2: a potential for therapeutic intervention. Breast Cancer Res, 201, 13(2): R39.
11.	Okabe A, Kiriyama Y, Suzuki S, et al. Short-term detection of gastric genotoxicity using the DNA double-strand break marker γ-H2AX. J Toxicol Pathol, 2019, 32(2): 91-99.
12.	Liu J, Li W, Zhang J, et al. Identification of key genes and long non-coding RNA associated ceRNA networks in hepatocellular carcinoma. PeerJ, 2019, 7: e8021.
13.	Yi S, Huang XY, Liu Y, et al. Identification of key candidate genes and pathways for relationship between ovarian cancer and diabetes mellitus using bioinformatical analysis. Asian Pac J Cancer Prev, 2019, 20(1): 145-155.
14.	Bretherick KL, Schuetz JM, Morton LM, et al. Sex- and subtype-specific analysis of H2AFX polymorphisms in non-Hodgkin lymphoma. PLoS One, 2013, 8(9): e74619.
15.	Ouillette P, Fossum S, Parkin B, et al. Aggressive chronic lymphocytic leukemia with elevated genomic complexity is associated with multiple gene defects in the response to DNA double-strand breaks. Clin Cancer Res, 2010, 16(3): 835-847.
16.	Carén H, Kryh H, Nethander M, et al. High-risk neuroblastoma tumors with 11q-deletion display a poor prognostic, chromosome instability phenotype with later onset. Proc Natl Acad Sci USA, 2010, 107(9): 4323-4328.
17.	Huang R, Liu Z, Tian T, et al. The construction and analysis of tumor-infiltrating immune cells and ceRNA networks in metastatic adrenal cortical carcinoma. Biosci Rep, 2020, 40(3): BSR20200049.
18.	Ma H, Liu C, Zhang S, et al. miR-328-3p promotes migration and invasion by targeting H2AFX in head and neck squamous cell carcinoma. J Cancer, 2021, 12(21): 6519-6530.
19.	Shrivastav M, De Haro LP, Nickoloff JA. Regulation of DNA double-strand break repair pathway choice. Cell Res, 2008, 18(1): 134-147.
20.	Kuo LJ, Yang LX. Gamma-H2AX - a novel biomarker for DNA double-strand breaks. In Vivo, 2008, 22(3): 305-309.
21.	Negrini S, Gorgoulis VG, Halazonetis TD. Genomic instability-an evolving hallmark of cancer. Nat Rev Mol Cell Biol, 2010, 11(3): 220-228.
22.	Wm B, Redon CE, Dickey JS, et al. GammaH2AX and cancer. Nat Rev Cancer, 2008, 8(12): 957-967.
23.	Wu C, Tong L, Wu C, et al. Two miRNA prognostic signatures of head and neck squamous cell carcinoma: a bioinformatic analysis based on the TCGA dataset. Cancer Med, 2020, 9(8): 2631-2642.
24.	Celeste A, Difilippantonio S, Difilippantonio MJ, et al. H2AX haploinsufficiency modifies genomic stability and tumor susceptibility. Cell, 2003, 114(3): 371-383.
25.	Bassing CH, Suh H, Ferguson DO, et al. Histone H2AX: a dosage-dependent suppressor of oncogenic translocations and tumors. Cell, 2003, 114(3): 359-370.
26.	Georgoulis A, Vorgias CE, Chrousos GP, et al. Genome instability and γH2AX. Int J Mol Sci, 2017, 18(9): 1979.
27.	Palla VV, Karaolanis G, Katafigiotis I, et al. gamma-H2AX: can it be established as a classical cancer prognostic factor?. Tumour Biol, 2017, 39(3): 1010428317695931.
28.	Corujo D, Buschbeck M. Post-translational modifications of H2A histone variants and their role in cancer. Cancers (Basel), 2018, 10(3): 59.
29.	Evert M, Frau M, Tomasi ML, et al. Deregulation of DNA-dependent protein kinase catalytic subunit contributes to human hepatocarcinogenesis development and has a putative prognostic value. Br J Cancer, 2013, 109(10): 2654-2664.
30.	Zhang Z, Li J, He T, et al. The competitive endogenous RNA regulatory network reveals potential prognostic biomarkers for overall survival in hepatocellular carcinoma. Cancer Sci, 2019, 110(9): 2905-2923.
31.	Ma CG, Xu WH, Xu Y, et al. Identification and validation of novel metastasis-related signatures of clear cell renal cell carcinoma using gene expression databases. Am J Transl Res, 2020, 12(8): 4108-4126.
32.	Zhang L, Chen J, Yang H, et al. Multiple microarray analyses identify key genes associated with the development of non-small cell lung cancer from chronic obstructive pulmonary disease. J Cancer, 2021, 12(4): 996-1010.
33.	Gao X, Tang RX, Xie QN, et al. The clinical value of miR-193a-3p in non-small cell lung cancer and its potential molecular mechanism explored in silico using RNA-sequencing and microarray data. FEBS Open Bio, 2018, 8(1): 94-109.

1. Guo T, Zhao S, Wang P, et al. YB-1 regulates tumor growth by promoting MACC1/c-Met pathway in human lung adenocarcinoma. Oncotarget, 2017, 8(29): 48110-48125.
2. Wei X, Zhang K, Qin H, et al. GMDS knockdown impairs cell proliferation and survival in human lung adenocarcinoma. BMC Cancer, 2018, 18(1): 600.
3. Ferrer I, Quintanal-Villalonga Á, Molina-Pinelo S, et al. MAP17 predicts sensitivity to platinum-based therapy, EGFR inhibitors and the proteasome inhibitor bortezomib in lung adenocarcinoma. J Exp Clin Cancer Res, 2018, 37(1): 195.
4. Liao M, Liu Q, Li B, et al. A group of long noncoding RNAs identified by data mining can predict the prognosis of lung adenocarcinoma. Cancer Sci, 2018, 109(12): 4033-4044.
5. Zhang Y, Sun L, Gao X, et al. RNF43 ubiquitinates and degrades phosphorylated E-cadherin by c-Src to facilitate epithelial-mesenchymal transition in lung adenocarcinoma. BMC Cancer, 2019, 19(1): 670.
6. He SY, Xi WJ, Wang X, et al. Identification of a combined RNA prognostic signature in adenocarcinoma of the lung. Med Sci Monit, 2019, 25: 3941-3956.
7. Ding F, Wang D, Li XK, et al. Overexpression of S100A14 contributes to malignant progression and predicts poor prognosis of lung adenocarcinoma. Thorac Cancer, 2018, 9(7): 827-835.
8. Lu JC, Wei QY, Bondy ML, et al. Genetic variants in the H2AFX promoter region are associated with risk of sporadic breast cancer in non-Hispanic white women aged ≤55 years. Breast Cancer Res Treat, 2008, 110(2): 357-366.
9. Podralska M, Ziółkowska-Suchanek I, Żurawek M, et al. Genetic variants in ATM, H2AFX and MRE11 genes and susceptibility to breast cancer in the Polish population. BMC Cancer, 2018, 18(1): 452.
10. Srivastava N, Manvati S, Srivastava A, et al. miR-24-2 controls H2AFX expression regardless of gene copy number alteration and induces apoptosis by targeting antiapoptotic gene BCL-2: a potential for therapeutic intervention. Breast Cancer Res, 201, 13(2): R39.
11. Okabe A, Kiriyama Y, Suzuki S, et al. Short-term detection of gastric genotoxicity using the DNA double-strand break marker γ-H2AX. J Toxicol Pathol, 2019, 32(2): 91-99.
12. Liu J, Li W, Zhang J, et al. Identification of key genes and long non-coding RNA associated ceRNA networks in hepatocellular carcinoma. PeerJ, 2019, 7: e8021.
13. Yi S, Huang XY, Liu Y, et al. Identification of key candidate genes and pathways for relationship between ovarian cancer and diabetes mellitus using bioinformatical analysis. Asian Pac J Cancer Prev, 2019, 20(1): 145-155.
14. Bretherick KL, Schuetz JM, Morton LM, et al. Sex- and subtype-specific analysis of H2AFX polymorphisms in non-Hodgkin lymphoma. PLoS One, 2013, 8(9): e74619.
15. Ouillette P, Fossum S, Parkin B, et al. Aggressive chronic lymphocytic leukemia with elevated genomic complexity is associated with multiple gene defects in the response to DNA double-strand breaks. Clin Cancer Res, 2010, 16(3): 835-847.
16. Carén H, Kryh H, Nethander M, et al. High-risk neuroblastoma tumors with 11q-deletion display a poor prognostic, chromosome instability phenotype with later onset. Proc Natl Acad Sci USA, 2010, 107(9): 4323-4328.
17. Huang R, Liu Z, Tian T, et al. The construction and analysis of tumor-infiltrating immune cells and ceRNA networks in metastatic adrenal cortical carcinoma. Biosci Rep, 2020, 40(3): BSR20200049.
18. Ma H, Liu C, Zhang S, et al. miR-328-3p promotes migration and invasion by targeting H2AFX in head and neck squamous cell carcinoma. J Cancer, 2021, 12(21): 6519-6530.
19. Shrivastav M, De Haro LP, Nickoloff JA. Regulation of DNA double-strand break repair pathway choice. Cell Res, 2008, 18(1): 134-147.
20. Kuo LJ, Yang LX. Gamma-H2AX - a novel biomarker for DNA double-strand breaks. In Vivo, 2008, 22(3): 305-309.
21. Negrini S, Gorgoulis VG, Halazonetis TD. Genomic instability-an evolving hallmark of cancer. Nat Rev Mol Cell Biol, 2010, 11(3): 220-228.
22. Wm B, Redon CE, Dickey JS, et al. GammaH2AX and cancer. Nat Rev Cancer, 2008, 8(12): 957-967.
23. Wu C, Tong L, Wu C, et al. Two miRNA prognostic signatures of head and neck squamous cell carcinoma: a bioinformatic analysis based on the TCGA dataset. Cancer Med, 2020, 9(8): 2631-2642.
24. Celeste A, Difilippantonio S, Difilippantonio MJ, et al. H2AX haploinsufficiency modifies genomic stability and tumor susceptibility. Cell, 2003, 114(3): 371-383.
25. Bassing CH, Suh H, Ferguson DO, et al. Histone H2AX: a dosage-dependent suppressor of oncogenic translocations and tumors. Cell, 2003, 114(3): 359-370.
26. Georgoulis A, Vorgias CE, Chrousos GP, et al. Genome instability and γH2AX. Int J Mol Sci, 2017, 18(9): 1979.
27. Palla VV, Karaolanis G, Katafigiotis I, et al. gamma-H2AX: can it be established as a classical cancer prognostic factor?. Tumour Biol, 2017, 39(3): 1010428317695931.
28. Corujo D, Buschbeck M. Post-translational modifications of H2A histone variants and their role in cancer. Cancers (Basel), 2018, 10(3): 59.
29. Evert M, Frau M, Tomasi ML, et al. Deregulation of DNA-dependent protein kinase catalytic subunit contributes to human hepatocarcinogenesis development and has a putative prognostic value. Br J Cancer, 2013, 109(10): 2654-2664.
30. Zhang Z, Li J, He T, et al. The competitive endogenous RNA regulatory network reveals potential prognostic biomarkers for overall survival in hepatocellular carcinoma. Cancer Sci, 2019, 110(9): 2905-2923.
31. Ma CG, Xu WH, Xu Y, et al. Identification and validation of novel metastasis-related signatures of clear cell renal cell carcinoma using gene expression databases. Am J Transl Res, 2020, 12(8): 4108-4126.
32. Zhang L, Chen J, Yang H, et al. Multiple microarray analyses identify key genes associated with the development of non-small cell lung cancer from chronic obstructive pulmonary disease. J Cancer, 2021, 12(4): 996-1010.
33. Gao X, Tang RX, Xie QN, et al. The clinical value of miR-193a-3p in non-small cell lung cancer and its potential molecular mechanism explored in silico using RNA-sequencing and microarray data. FEBS Open Bio, 2018, 8(1): 94-109.

West China Medical Journal

Expression and clinical significance of H2AFX gene in lung adenocarcinoma

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