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Loss of Expression of PTEN is Associated with Worse Prognosis in Patients with Cancer

  • Qiu, Zhi-Xin (Department of Respiratory Medicine, West China Hospital, Sichuan University) ;
  • Zhao, Shuang (Department of Respiratory Medicine, West China Hospital, Sichuan University) ;
  • Li, Lei (Department of Respiratory Medicine, West China Hospital, Sichuan University) ;
  • Li, Wei-Min (Department of Respiratory Medicine, West China Hospital, Sichuan University)
  • Published : 2015.06.26

Abstract

Background: The tumor suppressor phosphatase and tensin homolog (PTEN) is an important negative regulator of cell-survival signaling. However, available results for the prognostic value of PTEN expression in patients with cancer remain controversial. Therefore, a meta-analysis of published studies investigating this issue was performed. Materials and Methods: A literature search via PubMed and EMBASE databases was conducted. Statistical analysis was performed by using the STATA 12.0 (STATA Corp., College, TX). Data from eligible studies were extracted and included into the meta-analysis using a random effects model. Results: A total of 3,810 patients from 27 studies were included in the meta-analysis, 22 investigating the relationship between PTEN expression and overall survival (OS) using univariate analysis, and nine with multivariate analysis. The pooled hazard ratio (HR) for OS was 1.64 (95% confidence interval (CI): 1.32-2.05) by univariate analysis and 1.56 (95% CI: 1.20-2.03) by multivariate analysis. In addition, eight papers including two disease-free-survival analyses (DFSs), four relapse-free-survival analyses (RFSs), three progression-free-survival analyses (PFSs) and one metastasis-free-survival analysis (MFS) reported the effect of PTEN on survival. The results showed that loss of PTEN expression was significant correlated with poor prognosis, with a combined HR of 1.74 (95% CI: 1.24-2.44). Furthermore, in the stratified analysis by the year of publication, ethnicity, cancer type, method, cut-off value, median follow-up time and neoadjuvant therapy in which the study was conducted, we found that the ethnicity, cancer type, method, median follow-up time and neoadjuvant therapy are associated with prognosis. Conclusions: Our study shows that negative or loss of expression of PTEN is associated with worse prognosis in patients with cancer. However, adequately designed prospective studies need to be performed for confirmation.

Keywords

Cancer;PTEN;overall survival;meta-analysis

Acknowledgement

Supported by : Nature Science Foundation of China

References

  1. Jemal A, Bray F, Center MM, et al (2011). Global cancer statistics. CA Cancer J Clin, 61, 69-90. https://doi.org/10.3322/caac.20107
  2. Al-Saad S, Al-Shibli K, Donnem T, et al (2008). The prognostic impact of NF-kappaB p105, vimentin, E-cadherin and Par6 expression in epithelial and stromal compartment in non-small-cell lung cancer. Br J Cancer, 99, 1476-83. https://doi.org/10.1038/sj.bjc.6604713
  3. Sawai H, Yasuda A, Ochi N, et al (2008). Loss of PTEN expression is associated with colorectal cancer liver metastasis and poor patient survival. BMC Gastroenterol, 8, 56. https://doi.org/10.1186/1471-230X-8-56
  4. Ortega-Molina A, Serrano M (2013). PTEN in cancer, metabolism, and aging. Trends Endocrinol Metab, 24, 184-9. https://doi.org/10.1016/j.tem.2012.11.002
  5. Loupakis F, Pollina L, Stasi I, et al (2009). PTEN expression and KRAS mutations on primary tumors and metastases in the prediction of benefit from cetuximab plus irinotecan for patients with metastatic colorectal cancer. J Clin Oncol 27, 2622-9. https://doi.org/10.1200/JCO.2008.20.2796
  6. Yin Y, Shen WH (2008). PTEN: a new guardian of the genome. Oncogene, 27, 5443-53. https://doi.org/10.1038/onc.2008.241
  7. Parmar MK, Torri V, Stewart L (1998). Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med, 17, 2815-34. https://doi.org/10.1002/(SICI)1097-0258(19981230)17:24<2815::AID-SIM110>3.0.CO;2-8
  8. Lau J, Ioannidis JP, Schmid CH (1997). Quantitative synthesis in systematic reviews. Ann Intern Med, 127, 820-6. https://doi.org/10.7326/0003-4819-127-9-199711010-00008
  9. Higgins JP, Thompson SG (2002). Quantifying heterogeneity in a meta-analysis. Stat Med, 21, 1539-58. https://doi.org/10.1002/sim.1186
  10. Depowski PL, Rosenthal SI, Ross JS (2001). Loss of expression of the PTEN gene protein product is associated with poor outcome in breast cancer. Mod Pathol, 14, 672-6. https://doi.org/10.1038/modpathol.3880371
  11. Hu TH, Huang CC, Lin PR, et al (2003). Expression and prognostic role of tumor suppressor gene PTEN/MMAC1/TEP1 in hepatocellular carcinoma. Cancer, 97, 1929-40. https://doi.org/10.1002/cncr.11266
  12. Zheng H, Tsuneyama K, Takahashi H, et al (2007). Expression of PTEN and FHIT is involved in regulating the balance between apoptosis and proliferation in lung carcinomas. Anticancer Res, 27, 575-81.
  13. Pantuck AJ, Seligson DB, Klatte T, et al (2007). Prognostic relevance of the mTOR pathway in renal cell carcinoma: implications for molecular patient selection for targeted therapy. Cancer, 109, 2257-67. https://doi.org/10.1002/cncr.22677
  14. Bedolla R, Prihoda TJ, Kreisberg JI, et al (2007). Determining risk of biochemical recurrence in prostate cancer by immunohistochemical detection of PTEN expression and Akt activation. Clin Cancer Res, 13, 3860-7. https://doi.org/10.1158/1078-0432.CCR-07-0091
  15. Thorarinsdottir HK, Santi M, McCarter R, et al (2008). Protein expression of platelet-derived growth factor receptor correlates with malignant histology and PTEN with survival in childhood gliomas. Clin Cancer Res, 14, 3386-94. https://doi.org/10.1158/1078-0432.CCR-07-1616
  16. Razis E, Briasoulis E, Vrettou E, et al (2008) Potential value of PTEN in predicting cetuximab response in colorectal cancer: an exploratory study. BMC Cancer, 8, 234. https://doi.org/10.1186/1471-2407-8-234
  17. Chung JY, Hong SM, Choi BY, et al (2009) The expression of phospho-AKT, phospho-mTOR, and PTEN in extrahepatic cholangiocarcinoma. Clin Cancer Res, 15, 660-7. https://doi.org/10.1158/1078-0432.CCR-08-1084
  18. Yoshizawa A, Fukuoka J, Shimizu S, et al (2010). Overexpression of phospho-eIF4E is associated with survival through AKT pathway in non-small cell lung cancer. Clin Cancer Res, 16, 240-248. https://doi.org/10.1158/1078-0432.CCR-09-0986
  19. Sood A, McClain D, Maitra R, et al (2012). PTEN gene expression and mutations in the PIK3CA gene as predictors of clinical benefit to anti-epidermal growth factor receptor antibody therapy in patients with KRAS wild-type metastatic colorectal cancer. Clin Colorectal Cancer, 11, 143-150. https://doi.org/10.1016/j.clcc.2011.12.001
  20. Liang YM, Li XH, Li WM, et al (2012) Prognostic significance of PTEN, Ki-67 and CD44s expression patterns in gastrointestinal stromal tumors. World J Gastroenterol, 18: 1664-71. https://doi.org/10.3748/wjg.v18.i14.1664
  21. Gonzalez-Roibon ND, Chaux A, Al-Hussain T, et al (2013). Dysregulation of mammalian target of rapamycin pathway in plasmacytoid variant of urothelial carcinoma of the urinary bladder. Hum Pathol, 44, 612-622. https://doi.org/10.1016/j.humpath.2012.07.009
  22. Boeck S, Jung A, Laubender RP, et al (2013). EGFR pathway biomarkers in erlotinib-treated patients with advanced pancreatic cancer: translational results from the randomised, crossover phase 3 trial AIO-PK0104. Br J Cancer, 108, 469-76. https://doi.org/10.1038/bjc.2012.495
  23. Zhu X, Qin X, Fei M, et al (2013). Loss and reduced expression of PTEN correlate with advanced-stage gastric carcinoma. Exp Ther Med, 5, 57-64. https://doi.org/10.3892/etm.2012.749
  24. Jiang FN, He HC, Zhang YQ, et al (2013) An integrative proteomics and interaction network-based classifier for prostate cancer diagnosis. PLoS One, 8, 63941. https://doi.org/10.1371/journal.pone.0063941
  25. Song M, Chen D, Lu B, et al (2013) PTEN loss increases PD-L1 protein expression and affects the correlation between PDL1 expression and clinical parameters in colorectal cancer. PLoS One, 8, 65821. https://doi.org/10.1371/journal.pone.0065821
  26. Price TJ, Hardingham JE, Lee CK, et al (2013). Prognostic impact and the relevance of PTEN copy number alterations in patients with advanced colorectal cancer (CRC) receiving bevacizumab. Cancer Med, 2, 277-85. https://doi.org/10.1002/cam4.75
  27. Li Y, Cui J, Zhang CH, Yang DJ, et al (2013) High-expression of DJ-1 and loss of PTEN associated with tumor metastasis and correlated with poor prognosis of gastric carcinoma. Int J Med Sci, 10, 1689-97. https://doi.org/10.7150/ijms.7292
  28. Atreya CE, Sangale Z, Xu N, et al (2013) PTEN expression is consistent in colorectal cancer primaries and metastases and associates with patient survival. Cancer Med 2, 496-506. https://doi.org/10.1002/cam4.97
  29. Ferraldeschi R, Nava Rodrigues D, Riisnaes R, et al (2015) PTEN protein loss and clinical outcome from castration-resistant prostate cancer treated with abiraterone acetate. Eur Urol, 67, 795-802. https://doi.org/10.1016/j.eururo.2014.10.027
  30. Kessler T, Sahm F, Blaes J, et al (2015) Glioma cell VEGFR-2 confers resistance to chemotherapeutic and antiangiogenic treatments in PTEN-deficient glioblastoma. Oncotarget.
  31. Martins FC, Santiago I, Trinh A, et al (2014) Combined image and genomic analysis of high-grade serous ovarian cancer reveals PTEN loss as a common driver event and prognostic classifier. Genome Biol, 15, 526. https://doi.org/10.1186/s13059-014-0526-8
  32. Qiu ZX, Zhang K, Qiu XS, et al (2013) The prognostic value of phosphorylated AKT expression in non-small cell lung cancer: a meta-analysis. PLoS One, 8, 81451. https://doi.org/10.1371/journal.pone.0081451
  33. Song MS, Salmena L, Pandolfi PP (2012) The functions and regulation of the PTEN tumour suppressor. Nat Rev Mol Cell Biol, 13, 283-96. https://doi.org/10.1038/nrm3330
  34. Wang X, Jiang X (2008) PTEN: a default gate-keeping tumor suppressor with a versatile tail. Cell Res, 18, 807-16. https://doi.org/10.1038/cr.2008.83
  35. Sun L, Liu J, Yuan Q, et al (2014) Association between PTEN Gene IVS4 polymorphism and risk of cancer: a meta-analysis. PLoS One, 9, 98851. https://doi.org/10.1371/journal.pone.0098851
  36. Kase S, Sugio K, Yamazaki K, et al (2000) Expression of E-cadherin and beta-catenin in human non-small cell lung cancer and the clinical significance. Clin Cancer Res, 6, 4789-96.
  37. Barnett CM, Heinrich MC, Lim J, et al (2014) Genetic profiling to determine risk of relapse-free survival in high-risk localized prostate cancer. Clin Cancer Res, 20, 1306-1312. https://doi.org/10.1158/1078-0432.CCR-13-1775

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