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


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.


Cancer;PTEN;overall survival;meta-analysis


Supported by : Nature Science Foundation of China


  1. Jemal A, Bray F, Center MM, et al (2011). Global cancer statistics. CA Cancer J Clin, 61, 69-90.
  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.
  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.
  4. Ortega-Molina A, Serrano M (2013). PTEN in cancer, metabolism, and aging. Trends Endocrinol Metab, 24, 184-9.
  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.
  6. Yin Y, Shen WH (2008). PTEN: a new guardian of the genome. Oncogene, 27, 5443-53.
  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.<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.
  9. Higgins JP, Thompson SG (2002). Quantifying heterogeneity in a meta-analysis. Stat Med, 21, 1539-58.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  34. Wang X, Jiang X (2008) PTEN: a default gate-keeping tumor suppressor with a versatile tail. Cell Res, 18, 807-16.
  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.
  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.

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