Cross-validation of genes potentially associated with overall survival and drug resistance in ovarian cancer

Gao,Yutao; Liu,Xia; Li,Ting; Wei,Luwei; Yang,Antai; Lu,Yi; Zhang,Jian; Li,Li; Wang,Sumei; Yin,Fuqiang

doi:10.3892/or.2017.5534

Cross-validation of genes potentially associated with overall survival and drug resistance in ovarian cancer

Authors:
- Yutao Gao
- Xia Liu
- Ting Li
- Luwei Wei
- Antai Yang
- Yi Lu
- Jian Zhang
- Li Li
- Sumei Wang
- Fuqiang Yin
View Affiliations

Affiliations: Department of Gynaecology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China, Center for Translational Medicine, Guangxi Medical University, Nanning, Guangxi 530021, P.R. China, Life Sciences Institute, Guangxi Medical University, Nanning, Guangxi 530021, P.R. China, Key Laboratory of High-Incidence-Tumor Prevention and Treatment (Guangxi Medical University), Ministry of Education, Nanning, Guangxi 530021, P.R. China, The First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
Published online on: March 27, 2017 https://doi.org/10.3892/or.2017.5534
Pages: 3084-3092

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Ovarian cancer is the leading cause of death among malignancies of the female reproductive system. The 5-year survival rates of ovarian cancer (OC) patients are very poor as a result of recurrent disease and emergence of drug resistance; thus, studies to find predictive markers and factors for drug resistance are ongoing. In the present study, based on the microarrays from The Cancer Genome Atlas (TCGA), and the Gene Expression Omnibus (GEO) profiles covering 1648 OC patients, 11 out of 136 genes that were found to be significantly dysregulated in OC were associated with overall survival (OS) in 489 OC patients of the TCGA cohort. Of these genes, CRISP3, LYVE1, OVGP1 and BCHE were identified as independent prognostic factors, with decreased expression of the first three genes predicting shorter OS, and decreased BCHE predicting longer OS. OVGP1, BCHE and further two genes, CKAP2 and CLDN10, were consistently and remarkably associated with OS when the number of patients increased from 489 to 1583, with increased CKAP2 and decreased CLDN10 predicted shorter OS; combining the four genes provided better predictions. Associations among the four genes with OS in subgroups of OC were further verified. Downregulation of OVGP1 was significantly associated with shorter OS in all subgroups of OC patients, including subgroups of 752 patients treated with chemotherapy regimens containing taxol, 763 with both platin and taxol, 1364 with platin, 371 patients with grade 1-2 disease, 968 with grade 3 disease, 1148 with stage III-IV disease, and 439 with TP53 mutations. In addition, CKAP2 expression was significantly associated with shorter OS in 515 OC patients who had low CA125 levels. Furthermore, comprehensive analyses that including RT-qPCR, bioinformatics analysis and clinical data revealed an association of CKAP2, BCHE, CLDN10 and OVGP1 with drug resistance in OC. The genes identified in the present study might be prognostic factors as well as potential therapeutic targets in the treatment of OC.

View Figures

View References

1	Coleman RL, Monk BJ, Sood AK and Herzog TJ: Latest research and treatment of advanced-stage epithelial ovarian cancer. Nat Rev Clin Oncol. 10:211–224. 2013. View Article : Google Scholar : PubMed/NCBI
2	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2016. CA Cancer J Clin. 66:7–30. 2016. View Article : Google Scholar : PubMed/NCBI
3	Vaughan S, Coward JI, Bast RC Jr, Berchuck A, Berek JS, Brenton JD, Coukos G, Crum CC, Drapkin R, Etemadmoghadam D, et al: Rethinking ovarian cancer: Recommendations for improving outcomes. Nat Rev Cancer. 11:719–725. 2011. View Article : Google Scholar : PubMed/NCBI
4	Pliarchopoulou K and Pectasides D: Epithelial ovarian cancer: Focus on targeted therapy. Crit Rev Oncol Hematol. 79:17–23. 2011. View Article : Google Scholar : PubMed/NCBI
5	Cannistra SA: Cancer of the ovary. N Engl J Med. 351:2519–2529. 2004. View Article : Google Scholar : PubMed/NCBI
6	Holohan C, Van Schaeybroeck S, Longley DB and Johnston PG: Cancer drug resistance: An evolving paradigm. Nat Rev Cancer. 13:714–726. 2013. View Article : Google Scholar : PubMed/NCBI
7	Yin F, Liu L, Liu X, Li G, Zheng L, Li D, Wang Q, Zhang W and Li L: Downregulation of tumor suppressor gene ribonuclease T2 and gametogenetin binding protein 2 is associated with drug resistance in ovarian cancer. Oncol Rep. 32:362–372. 2014.PubMed/NCBI
8	Gyorffy B, Lánczky A and Szállási Z: Implementing an online tool for genome-wide validation of survival-associated biomarkers in ovarian-cancer using microarray data from 1287 patients. Endocr Relat Cancer. 19:197–208. 2012. View Article : Google Scholar : PubMed/NCBI
9	Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, et al: The cBio cancer genomics portal: An open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2:401–404. 2012. View Article : Google Scholar : PubMed/NCBI
10	Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, Sun Y, Jacobsen A, Sinha R, Larsson E, et al: Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 6:pl12013. View Article : Google Scholar : PubMed/NCBI
11	Edgar R, Domrachev M and Lash AE: Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 30:207–210. 2002. View Article : Google Scholar : PubMed/NCBI
12	Liu X, Zou J, Su J, Lu Y, Zhang J, Li L and Yin F: Downregulation of transient receptor potential cation channel, subfamily C, member 1 contributes to drug resistance and high histological grade in ovarian cancer. Int J Oncol. 48:243–252. 2016.PubMed/NCBI
13	Mostafavi S, Ray D, Warde-Farley D, Grouios C and Morris Q: GeneMANIA: A real-time multiple association network integration algorithm for predicting gene function. Genome Biol. 9:(Suppl 1). S42008. View Article : Google Scholar : PubMed/NCBI
14	Warde-Farley D, Donaldson SL, Comes O, Zuberi K, Badrawi R, Chao P, Franz M, Grouios C, Kazi F, Lopes CT, et al: The GeneMANIA prediction server: Biological network integration for gene prioritization and predicting gene function. Nucleic Acids Res. 38:(Web Server). W214–W220. 2010. View Article : Google Scholar : PubMed/NCBI
15	Jenssen TK, Laegreid A, Komorowski J and Hovig E: A literature network of human genes for high-throughput analysis of gene expression. Nat Genet. 28:21–28. 2001. View Article : Google Scholar : PubMed/NCBI
16	Hedditch EL, Gao B, Russell AJ, Lu Y, Emmanuel C, Beesley J, Johnatty SE, Chen X, Harnett P, George J, et al: Australian Ovarian Cancer Study Group: ABCA transporter gene expression and poor outcome in epithelial ovarian cancer. J Natl Cancer Inst. 106:1062014. View Article : Google Scholar
17	Liu X, Gao Y, Zhao B, Li X, Lu Y, Zhang J, Li D, Li L and Yin F: Discovery of microarray-identified genes associated with ovarian cancer progression. Int J Oncol. 46:2467–2478. 2015.PubMed/NCBI
18	Li M, Balch C, Montgomery JS, Jeong M, Chung JH, Yan P, Huang TH, Kim S and Nephew KP: Integrated analysis of DNA methylation and gene expression reveals specific signaling pathways associated with platinum resistance in ovarian cancer. BMC Med Genomics. 2:342009. View Article : Google Scholar : PubMed/NCBI
19	Yin F, Liu X, Li D, Wang Q, Zhang W and Li L: Tumor suppressor genes associated with drug resistance in ovarian cancer (Review). Oncol Rep. 30:3–10. 2013.PubMed/NCBI
20	Liu X, Gao Y, Lu Y, Zhang J, Li L and Yin F: Oncogenes associated with drug resistance in ovarian cancer. J Cancer Res Clin Oncol. 141:381–395. 2015. View Article : Google Scholar : PubMed/NCBI
21	Liu X, Gao Y, Lu Y, Zhang J, Li L and Yin F: Upregulation of NEK2 is associated with drug resistance in ovarian cancer. Oncol Rep. 31:745–754. 2014.PubMed/NCBI
22	Liu X, Gao Y, Lu Y, Zhang J, Li L and Yin F: Downregulation of NEK11 is associated with drug resistance in ovarian cancer. Int J Oncol. 45:1266–1274. 2014.PubMed/NCBI
23	Yin F, Liu X, Li D, Wang Q, Zhang W and Li L: Bioinformatic analysis of chemokine (C-C motif) ligand 21 and SPARC-like protein 1 revealing their associations with drug resistance in ovarian cancer. Int J Oncol. 42:1305–1316. 2013.PubMed/NCBI
24	Wong KF, Xu Z, Chen J, Lee NP and Luk JM: Circulating markers for prognosis of hepatocellular carcinoma. Expert Opin Med Diagn. 7:319–329. 2013. View Article : Google Scholar : PubMed/NCBI
25	Kim HS, Koh JS, Choi YB, Ro J, Kim HK, Kim MK, Nam BH, Kim KT, Chandra V, Seol HS, et al: Chromatin CKAP2, a new proliferation marker, as independent prognostic indicator in breast cancer. PLoS One. 9:e981602014. View Article : Google Scholar : PubMed/NCBI
26	Kim YW, Eom BW, Kook MC, Kim HS, Kim MK, Hwang HL, Chandra V, Poojan S, Song Y, Koh JS, et al: Clinical implications of proliferation activity in T1 or T2 male gastric cancer patients. Exp Mol Med. 47:e1932015. View Article : Google Scholar : PubMed/NCBI
27	Zhang Z, Wang A, Sun B, Zhan Z, Chen K and Wang C: Expression of CLDN1 and CLDN10 in lung adenocarcinoma in situ and invasive lepidic predominant adenocarcinoma. J Cardiothorac Surg. 8:952013. View Article : Google Scholar : PubMed/NCBI
28	Koie T, Ohyama C, Hatakeyama S, Imai A, Yoneyama T, Hashimoto Y, Yoneyama T, Tobisawa Y, Hosogoe S, Yamamoto H, et al: Significance of preoperative butyrylcholinesterase as an independent predictor of biochemical recurrence-free survival in patients with prostate cancer treated with radical prostatectomy. Int J Clin Oncol. 21:379–383. 2016. View Article : Google Scholar : PubMed/NCBI
29	Koie T, Ohyama C, Yamamoto H, Hatakeyama S, Imai A, Yoneyama T, Hashimoto Y, Kitayam M and Hirota K: Significance of preoperative butyrylcholinesterase as an independent predictor of survival in patients with muscle-invasive bladder cancer treated with radical cystectomy. Urol Oncol. 32:820–825. 2014. View Article : Google Scholar : PubMed/NCBI
30	Willis S, Villalobos VM, Gevaert O, Abramovitz M, Williams C, Sikic BI and Leyland-Jones B: Single gene prognostic biomarkers in ovarian cancer: A meta-analysis. PLoS One. 11:e01491832016. View Article : Google Scholar : PubMed/NCBI
31	Nagele F, Petru E, Medl M, Kainz C, Graf AH and Sevelda P: Preoperative CA 125: An independent prognostic factor in patients with stage I epithelial ovarian cancer. Obstet Gynecol. 86:259–264. 1995. View Article : Google Scholar : PubMed/NCBI
32	Tang A, Kondalsamy-Chennakesavan S, Ngan H, Zusterzeel P, Quinn M, Carter J, Leung Y and Obermair A: Prognostic value of elevated preoperative serum CA125 in ovarian tumors of low malignant potential: A multinational collaborative study (ANZGOG0801). Gynecol Oncol. 126:36–40. 2012. View Article : Google Scholar : PubMed/NCBI
33	Poersch A, Grassi ML, Carvalho VP, Lanfredi GP, Palma CS, Greene LJ, de Sousa CB, Carrara HH, Dos Candido Reis FJ and Faça VM: A proteomic signature of ovarian cancer tumor fluid identified by highthroughput and verified by targeted proteomics. J Proteomics. 145:226–236. 2016. View Article : Google Scholar : PubMed/NCBI
34	Seo HW, Rengaraj D, Choi JW, Ahn SE, Song YS, Song G and Han JY: Claudin 10 is a glandular epithelial marker in the chicken model as human epithelial ovarian cancer. Int J Gynecol Cancer. 20:1465–1473. 2010.PubMed/NCBI