GENETIC TESTING AND MOLECULAR BIOMARKERS Volume 18, Number 4, 2014 ª Mary Ann Liebert, Inc. Pp. 279–285 DOI: 10.1089/gtmb.2013.0447
Relationship of PTTG Expression with Tumor Invasiveness and Microvessel Density of Pituitary Adenomas: A Meta-Analysis Yan Li,1 Li-Ping Zhou,2 Ping Ma,1 Cheng-Guang Sui,1 Fan-Dong Meng,1 Xin Tian,1 Li-Ye Fu,1 and You-Hong Jiang1
Aims: Many existing studies have demonstrated that pituitary tumor transforming gene (PTTG) expression may contribute to the development of pituitary adenomas (PAs), but individually published studies showed inconclusive results. This meta-analysis aimed to derive a more precise estimation of the relationships of PTTG expression with tumor invasiveness and microvessel density of pituitary adenomas. Methods: We searched CISCOM, CINAHL, Web of Science, PubMed, Google Scholar, EBSCO, Cochrane Library, and CBM databases from inception through September 1st, 2013. Meta-analysis was performed using the STATA 12.0 software. The crude odds ratio (OR) with 95% confidence interval (CI) was calculated. Results: Fifteen clinical cohort studies were included with a total of 752 pituitary adenoma patients. The meta-analysis results revealed that patients with invasive pituitary adenomas had higher positive expression of PTTG than those of noninvasive patients (OR = 6.68, 95% CI = 3.72–11.99, p < 0.001). We also found a significant difference in the microvessel density between invasive and noninvasive patients (OR = 1.81, 95% CI = 0.39–3.23, p < 0.001). No publication bias was detected in this meta-analysis (all p > 0.05). Conclusion: The present meta-analysis suggests that PTTG expression may be associated with tumor invasiveness and microvessel density of pituitary adenomas. Thus, detection of PTTG expression may be useful for the prediction of malignancy degree in pituitary adenomas.
Introduction
P
ituitary adenomas (PAs), abnormal growths in the pituitary gland, represent about 15% of primary intracranial neoplasms and are the second most common type of intracranial tumor by histology in young adults in the 20–34year-age range (Gadelha et al., 2013). For many years, pituitary adenomas have been considered a rare clinical entity based on certain population studies that revealed a prevalence of 1:3571–1:5263 or even lower (Dolecek et al., 2012). Generally, pituitary adenomas are benign, but exhibit invasive or recurrent growth (Melmed, 2003). Like other differentiated neuroendocrine tissues, the pituitary gland displays trophic hormone cell plasticity in response to physiological and homeostatic demands (Cruz-Soto et al., 2002). The pituitary gland responds to complex central and peripheral signals by two mechanisms: (1) trophic hormone secretion is exquisitely controlled to regulate homeostasis; (2) developmental or acquired pituitary signals may elicit plastic pituitary growth responses, consisting of hypoplasia, hyperplasia, or adenoma formation (Ezzat et al., 2004; Daly et al., 2006). Pituitary adenomas arise from monoclonal growth and intrinsic
genetic defects, which are associated with oncogenes, suppressor genes, and genes charging of differentiation (Ye et al., 2011; Trivellin et al., 2012; Yoon et al., 2012). Growth factors of hypothalamic or pituitary origin may also act on aberrant cells, contributing to their proliferation (Chesnokova et al., 2007). Recently, a large number of studies suggest that expression of the pituitary tumor transforming gene (PTTG) plays a key role in the development of pituitary adenomas. Human PTTG, a protein of 202 amino acids, is a newly discovered biological marker of malignancy grades in several forms of cancer, particularly endocrine malignancies, such as pituitary adenomas (Chesnokova and Melmed, 2010). PTTG, initially isolated from pituitary tumor cells, is abundantly expressed in the pituitary, breast, thyroid, endometrial, esophageal, and colorectal tumors, and the levels of PTTG expression are concurrent with tumor invasiveness, recurrence, and poor prognosis (Vlotides et al., 2007). Previous studies have investigated that PTTG as an important paracrine growth factor involved in early lactotrope transformation and onset of angiogenesis (Cristina et al., 2007; Shah and Kakar, 2011; Recouvreux et al., 2013). Overexpression of PTTG causes in vitro cell transformation, results
1 Molecular Oncology Department of Cancer Research Institution and 2Department of Laboratory Medicine, The First Hospital of China Medical University, Shenyang, People’s Republic of China.
279
280
LI ET AL.
FIG. 1. Flowchart shows the study selection procedure. Fifteen cohort studies were included in this metaanalysis.
in vivo tumor formation, and stimulated basic fibroblast growth factor (bFGF) expression and secretion (Chesnokova et al., 2011). A number of studies have shown that expression of PTTG may contribute to the development and progression of pituitary adenomas, but their results were uncertain (Hu et al., 2006; Li et al., 2007; He et al., 2008). Therefore, we performed a meta-analysis of all available data to provide a more comprehensive and reliable conclusion on the roles of PTTG expression in human pituitary adenomas.
Materials and Methods Literature search strategy
We searched CISCOM, CINAHL, Web of Science, PubMed, Google Scholar, EBSCO, Cochrane Library, and CBM databases from inception through September 1st, 2013 without language restrictions. The following keywordsand MeSH terms were used: ‘‘pituitary adenoma,’’ ‘‘pituitary adenomas,’’ ‘‘pituitary tumor,’’ ‘‘pituitary macroadenoma,’’ ‘‘PTTG,’’ ‘‘pituitary tumor transforming gene,’’ ‘‘hPTTG,’’ and so on. We also performed a manual search to find other potential articles. Selection criteria
FIG. 2. The distribution of the number of topic-related reports in the electronic database during the last decade.
In our meta-analysis, included studies must meet all the following criteria: (1) the study design must be a clinical cohort study; (2) the study must relate to the roles of PTTG expression in human pituitary adenoma; (3) all patients must conform to the diagnostic criteria of pituitary adenoma; (4) the study must provide sufficient information about the PTTG expression and clinical or histopathological characteristics of pituitary adenomas. If the study could not meet the inclusion criteria, it would be excluded. The most recent or the largest sample size publication was included when the authors published several studies using the same subjects. Any disagreements were resolved through discussions and subsequent consensus.
PTTG EXPRESSION AND PITUITARY ADENOMAS
281
Table 1. Baseline Characteristics and Methodological Quality of All Included Studies Tumor invasiveness First author
Year
Invasion PAs
Noninvasion PAs
Power
Gender (M/F)
Age (years)
NOS score
Sun Zhang Shen Mo Wu Zhou Wang Li He Li Xiong Hu Li Wang Liu
2013 2012 2012 2011 2010 2008 2008 2008 2008 2007 2006 2006 2006 2005 2004
29 22 45 28 26 29 21 34 15 26 30 12 30 38 20
23 41 18 22 22 20 27 17 28 24 25 28 25 17 10
0.503 0.517 0.517 0.500 0.497 0.499 0.497 0.501 0.491 0.500 0.507 0.487 0.507 0.507 0.473
29/23 — 27/36 23/27 26/22 23/26 28/20 28/23 21/27 17/33 33/27 17/23 — 20/35 18/12
65.0 (60–72) — 41 (8–67) 14–68 46.0 – 0.5 — 36.5 – 9.7 39.0 (17–68) 47.5 (19–73) 42.7 – 11.7 39.2 (17–70) 45.5 (17–74) — 36.0 (22–65) 41.5 (20–72)
7 5 8 7 7 6 7 7 7 7 7 7 6 7 5
PAs, pituitary adenomas; M, male; F, female; NOS, the Newcastle-Ottawa Scale.
Data extraction
Statistical analysis
Using a standardized form, relevant data were systematically extracted from all included studies by two researchers. The standardized form included the following items: language of publication, publication year of article, the first author’s surname, geographical location, design of study, sample size, the source of the subjects, source of samples, detection methods, PTTG expression, and so forth.
We performed the meta-analysis by using the STATA 12.0 software (Stata Corp., College Station, TX). The standardized mean differences or odds ratios (ORs) with 95% confidence interval (CI) were calculated. The Z test was used to estimate the statistical significance of ORs. Power calculations were done by PS Power and Sample Size Calculations (Dupont and Plummer, 1990). The Cochran’s Q-statistic and I2 test were used to evaluate potential heterogeneity between studies (Biggerstaff and Jackson, 2008). If the Q-test showed a p < 0.05 or the I2 test exhibits > 50%, which indicates significant heterogeneity, the random-effects model was conducted, or else the fixed-effects model was used. We also performed subgroup and meta-regression analyses to explore the potential sources of heterogeneity. Sensitivity analysis was performed by omitting each study in turn to valuate the influence of single studies on the overall estimate.
Quality assessment
We evaluated the methodological quality of the included studies according to the Newcastle-Ottawa Scale (NOS) criteria (Stang, 2010). The NOS criteria included three aspects: (1) subject selection: 0–4 scores; (2) comparability of subject: 0–2 scores; and (3) clinical outcome: 0–3 scores. The NOS score ranged from 0 to 9; and a score ‡ 7 indicates good quality.
FIG. 3. Forest plots for the relationship between pituitary tumor transforming gene (PTTG) expression and tumor invasiveness of pituitary adenomas.
282
LI ET AL.
FIG. 4. Forest plots for the relationship between PTTG expression and microvessel density of pituitary adenomas.
The Begger’s funnel plots and Egger’s linear regression test were conducted to investigate publication bias (Peters et al., 2006). Results Baseline characteristics of included studies
A total of 986 articles relevant to the searched keywords were initially identified. The titles and abstracts of all articles were reviewed and 529 were excluded; full texts and data integrity were then reviewed and another 432 articles were excluded. Finally, 15 clinical cohort studies were included in this meta-analysis (Liu et al., 2004; Wang et al., 2005, 2008; Hu et al., 2006; Li et al., 2006, 2007, 2008; Xiong et al., 2006; He et al., 2008; Zhou and Chen, 2008; Wu et al., 2010; Mo et al., 2011; Shen and Cui, 2012; Zhang et al., 2012; Sun et al., 2013). Publication years of the eligible studies ranged from 2004 to 2013. The selection process of eligible studies is shown in Figure 1. The distribution of the number of topicrelated literatures in the electronic database during the last decade is shown in Figure 2. A total of 752 pituitary adenoma patients, who were Asians, were involved in this meta-analysis, including 405 patients with invasive pituitary adenomas
FIG. 5. Sensitivity analysis of the associations between PTTG expression and biological characteristics of pituitary adenomas. Results were computed by omitting each study in turn. Meta-analysis random-effects estimates (exponential form) were used. The two ends of the dotted lines represent the 95% confidence interval.
and 347 patients with noninvasive pituitary adenomas. There were 170 patients from the experiment in microvessel density analysis, including 112 invasive and 58 noninvasive patients. All the power for the sample size of included studies was higher than 0.60 except two studies (Hu et al., 2006; Li et al., 2008). The classical immunohistochemistry method was performed to detect PTTG protein expression in all included studies. We summarized the study characteristics and methodological quality in Table 1. Quantitative data synthesis
The random-effects model was conducted due to significant heterogeneity that existed between studies. The metaanalysis results showed that patients with invasive pituitary adenomas had a higher positive expression of PTTG than those of noninvasive patients (OR = 6.68, 95% CI = 3.72* 11.99, p < 0.001) (Fig. 3). We also found a significant difference in microvessel density between invasive and noninvasive patients (OR = 1.81, 95% CI = 0.39*3.23, p < 0.001) (Fig. 4). Sensitivity analysis was performed to assess the influence of each individual study on the pooled ORs by omitting each individual study. The analysis results suggested that no
PTTG EXPRESSION AND PITUITARY ADENOMAS
individual studies significantly affected the pooled ORs (Fig. 5), indicating a statistically robust result. The shapes of Begger’s funnel plots did not reveal any evidence of obvious asymmetry (Fig. 6). The Egger’s test also displayed no significant statistical evidence of publication bias (t = - 1.59, p = 0.135). Discussion
Pituitary adenomas arise from epithelial pituitary cells and account for 10–15% of all intracranial tumors (Cuny et al., 2013). With the development of molecular biology and cytogenetic techniques, substantial advances in the understanding of pathogenesis and progression of pituitary tumors have been achieved (Fedele and Fusco, 2013; Jaffrain-Rea and Beckers, 2013; Zhou, 2013). Abundant studies have evaluated the roles of PTTG expression in human pituitary adenomas (McCabe et al., 2003; Hsueh et al., 2013; Zhou et al., 2013). PTTG is an oncogene found in pituitary adenomas, and its encoded proteins are involved in a variety of physiological processes, such as gene activation, cell transformation, angiogenesis, apoptosis, DNA repair, and genetic stability control (Zhang et al., 1999). Tfelt-Hansen et al. (2006) have inferred that PTTG is one of the key factors in the occurrence, proliferation, and invasion of a variety of tumors. Zhang et al. (1999) concluded that the ubiquitous and prevalent expression of pituitary adenoma PTTG suggests that PTTG plays a role in pituitary tumorigenesis and invasiveness. The important role of PTTG prompted researchers to investigate the relationship between PTTG and the biological characteristics of pituitary tumors (Gagliano et al., 2013; Hsueh et al., 2013). Raverot et al. (2010) have also demonstrated that expression of the PTTG was related to invasiveness of prolactin adenomas. In the present meta-analysis, we evaluated the roles of PTTG expression in human pituitary adenomas. Finally, 15 independent cohort studies were included with a total of 752 pituitary adenoma patients. Our meta-analysis results suggested that high expression of PTTG was closely associated with enhanced invasiveness of pituitary adenomas, indicating
283
that a high expression level of PTTG was related to the invasiveness of pituitary adenomas. We also observed that the microvessel density in invasive patients was significantly higher compared with noninvasive patients, suggesting that PTTG expression could be an indicator of the tumor proliferative activity and might serve as a potential marker of poor prognosis and tumor recurrence for patients with pituitary adenomas. A study by Filippella et al. (2006) has suggested the association between PTTG and the recurrence of pituitary adenomas in humans, and set the expression level of PTTG more than 3% as the standard for the confirmation of recurrence. These claims are in accordance with our findings in the present meta-analysis. Although the exact function of PTTG in the development and progression of pituitary adenomas is not fully understood yet, a potential explanation might be that high expression of PTTG could cause cell transformation and induce aneuploidy with the abundance of PTTG possibly leading to the dysregulation of G2/M checkpoint surveillance, leading to abnormal mitosis, and leading to chromosomal instability (Yu et al., 2003; Chesnokova et al., 2005; Donangelo et al., 2006; Chesnokova et al., 2007). All in all, our findings were consistent with previous studies that PTTG expression was associated with biological characteristics of human pituitary adenomas and might play important roles in the development of pituitary tumors, suggesting that PTTG expression may be a useful biomarker for pituitary adenomas. This is the first meta-analysis focused on the relationships between PTTG expression and biological characteristics of pituitary tumors. Nevertheless, our meta-analysis also had some limitations. First, our results may not provide sufficient statistical power to estimate the roles of PTTG expression in human pituitary adenomas due to the relatively small sample size. Second, meta-analysis is a retrospective study that may lead to subject selection bias, thereby affecting the reliability of our results. Third, our meta-analysis failed to obtain original data from the included studies, which may limit further evaluation of potential roles of PTTG in pituitary adenoma patients. Importantly, the inclusion criteria of cases and controls were not well defined in all included studies, which might also influence our results. In conclusion, our meta-analysis suggests that PTTG expression may be associated with tumor invasiveness and microvessel density of pituitary adenomas. Thus, detection of PTTG expression may be useful for prediction of malignancy degree in pituitary adenomas. However, due to the limitations mentioned above, further detailed studies are still required to confirm our findings. Acknowledgments
FIG. 6. Begger’s funnel plots of the associations between PTTG expression and biological characteristics of pituitary adenomas. Each point represents a separate study for the indicated association. Log [OR], natural logarithm of odds ratio. Horizontal line, mean magnitude of the effect.
The authors would also like to thank all their colleagues working in the Department of Laboratory Medicine and Molecular Oncology Department of Cancer Research Institution, The First Hospital of China Medical University. This study was supported by a grant from the Science and Technology Research Project of the Higher Education Department of Liaoning Province (No. L2010695). Author Disclosure Statement
The authors have declared that no competing interests exist.
284 References
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Address correspondence to: You-Hong Jiang, MD Molecular Oncology Department of Cancer Research Institution The First Hospital of China Medical University Nanjing Street No. 155 Heping District Shenyang 110001 People’s Republic of China E-mail: [email protected]
Relationship of PTTG Expression with Tumor Invasiveness and Microvessel Density of Pituitary Adenomas: A Meta-Analysis Yan Li,1 Li-Ping Zhou,2 Ping Ma,1 Cheng-Guang Sui,1 Fan-Dong Meng,1 Xin Tian,1 Li-Ye Fu,1 and You-Hong Jiang1
Aims: Many existing studies have demonstrated that pituitary tumor transforming gene (PTTG) expression may contribute to the development of pituitary adenomas (PAs), but individually published studies showed inconclusive results. This meta-analysis aimed to derive a more precise estimation of the relationships of PTTG expression with tumor invasiveness and microvessel density of pituitary adenomas. Methods: We searched CISCOM, CINAHL, Web of Science, PubMed, Google Scholar, EBSCO, Cochrane Library, and CBM databases from inception through September 1st, 2013. Meta-analysis was performed using the STATA 12.0 software. The crude odds ratio (OR) with 95% confidence interval (CI) was calculated. Results: Fifteen clinical cohort studies were included with a total of 752 pituitary adenoma patients. The meta-analysis results revealed that patients with invasive pituitary adenomas had higher positive expression of PTTG than those of noninvasive patients (OR = 6.68, 95% CI = 3.72–11.99, p < 0.001). We also found a significant difference in the microvessel density between invasive and noninvasive patients (OR = 1.81, 95% CI = 0.39–3.23, p < 0.001). No publication bias was detected in this meta-analysis (all p > 0.05). Conclusion: The present meta-analysis suggests that PTTG expression may be associated with tumor invasiveness and microvessel density of pituitary adenomas. Thus, detection of PTTG expression may be useful for the prediction of malignancy degree in pituitary adenomas.
Introduction
P
ituitary adenomas (PAs), abnormal growths in the pituitary gland, represent about 15% of primary intracranial neoplasms and are the second most common type of intracranial tumor by histology in young adults in the 20–34year-age range (Gadelha et al., 2013). For many years, pituitary adenomas have been considered a rare clinical entity based on certain population studies that revealed a prevalence of 1:3571–1:5263 or even lower (Dolecek et al., 2012). Generally, pituitary adenomas are benign, but exhibit invasive or recurrent growth (Melmed, 2003). Like other differentiated neuroendocrine tissues, the pituitary gland displays trophic hormone cell plasticity in response to physiological and homeostatic demands (Cruz-Soto et al., 2002). The pituitary gland responds to complex central and peripheral signals by two mechanisms: (1) trophic hormone secretion is exquisitely controlled to regulate homeostasis; (2) developmental or acquired pituitary signals may elicit plastic pituitary growth responses, consisting of hypoplasia, hyperplasia, or adenoma formation (Ezzat et al., 2004; Daly et al., 2006). Pituitary adenomas arise from monoclonal growth and intrinsic
genetic defects, which are associated with oncogenes, suppressor genes, and genes charging of differentiation (Ye et al., 2011; Trivellin et al., 2012; Yoon et al., 2012). Growth factors of hypothalamic or pituitary origin may also act on aberrant cells, contributing to their proliferation (Chesnokova et al., 2007). Recently, a large number of studies suggest that expression of the pituitary tumor transforming gene (PTTG) plays a key role in the development of pituitary adenomas. Human PTTG, a protein of 202 amino acids, is a newly discovered biological marker of malignancy grades in several forms of cancer, particularly endocrine malignancies, such as pituitary adenomas (Chesnokova and Melmed, 2010). PTTG, initially isolated from pituitary tumor cells, is abundantly expressed in the pituitary, breast, thyroid, endometrial, esophageal, and colorectal tumors, and the levels of PTTG expression are concurrent with tumor invasiveness, recurrence, and poor prognosis (Vlotides et al., 2007). Previous studies have investigated that PTTG as an important paracrine growth factor involved in early lactotrope transformation and onset of angiogenesis (Cristina et al., 2007; Shah and Kakar, 2011; Recouvreux et al., 2013). Overexpression of PTTG causes in vitro cell transformation, results
1 Molecular Oncology Department of Cancer Research Institution and 2Department of Laboratory Medicine, The First Hospital of China Medical University, Shenyang, People’s Republic of China.
279
280
LI ET AL.
FIG. 1. Flowchart shows the study selection procedure. Fifteen cohort studies were included in this metaanalysis.
in vivo tumor formation, and stimulated basic fibroblast growth factor (bFGF) expression and secretion (Chesnokova et al., 2011). A number of studies have shown that expression of PTTG may contribute to the development and progression of pituitary adenomas, but their results were uncertain (Hu et al., 2006; Li et al., 2007; He et al., 2008). Therefore, we performed a meta-analysis of all available data to provide a more comprehensive and reliable conclusion on the roles of PTTG expression in human pituitary adenomas.
Materials and Methods Literature search strategy
We searched CISCOM, CINAHL, Web of Science, PubMed, Google Scholar, EBSCO, Cochrane Library, and CBM databases from inception through September 1st, 2013 without language restrictions. The following keywordsand MeSH terms were used: ‘‘pituitary adenoma,’’ ‘‘pituitary adenomas,’’ ‘‘pituitary tumor,’’ ‘‘pituitary macroadenoma,’’ ‘‘PTTG,’’ ‘‘pituitary tumor transforming gene,’’ ‘‘hPTTG,’’ and so on. We also performed a manual search to find other potential articles. Selection criteria
FIG. 2. The distribution of the number of topic-related reports in the electronic database during the last decade.
In our meta-analysis, included studies must meet all the following criteria: (1) the study design must be a clinical cohort study; (2) the study must relate to the roles of PTTG expression in human pituitary adenoma; (3) all patients must conform to the diagnostic criteria of pituitary adenoma; (4) the study must provide sufficient information about the PTTG expression and clinical or histopathological characteristics of pituitary adenomas. If the study could not meet the inclusion criteria, it would be excluded. The most recent or the largest sample size publication was included when the authors published several studies using the same subjects. Any disagreements were resolved through discussions and subsequent consensus.
PTTG EXPRESSION AND PITUITARY ADENOMAS
281
Table 1. Baseline Characteristics and Methodological Quality of All Included Studies Tumor invasiveness First author
Year
Invasion PAs
Noninvasion PAs
Power
Gender (M/F)
Age (years)
NOS score
Sun Zhang Shen Mo Wu Zhou Wang Li He Li Xiong Hu Li Wang Liu
2013 2012 2012 2011 2010 2008 2008 2008 2008 2007 2006 2006 2006 2005 2004
29 22 45 28 26 29 21 34 15 26 30 12 30 38 20
23 41 18 22 22 20 27 17 28 24 25 28 25 17 10
0.503 0.517 0.517 0.500 0.497 0.499 0.497 0.501 0.491 0.500 0.507 0.487 0.507 0.507 0.473
29/23 — 27/36 23/27 26/22 23/26 28/20 28/23 21/27 17/33 33/27 17/23 — 20/35 18/12
65.0 (60–72) — 41 (8–67) 14–68 46.0 – 0.5 — 36.5 – 9.7 39.0 (17–68) 47.5 (19–73) 42.7 – 11.7 39.2 (17–70) 45.5 (17–74) — 36.0 (22–65) 41.5 (20–72)
7 5 8 7 7 6 7 7 7 7 7 7 6 7 5
PAs, pituitary adenomas; M, male; F, female; NOS, the Newcastle-Ottawa Scale.
Data extraction
Statistical analysis
Using a standardized form, relevant data were systematically extracted from all included studies by two researchers. The standardized form included the following items: language of publication, publication year of article, the first author’s surname, geographical location, design of study, sample size, the source of the subjects, source of samples, detection methods, PTTG expression, and so forth.
We performed the meta-analysis by using the STATA 12.0 software (Stata Corp., College Station, TX). The standardized mean differences or odds ratios (ORs) with 95% confidence interval (CI) were calculated. The Z test was used to estimate the statistical significance of ORs. Power calculations were done by PS Power and Sample Size Calculations (Dupont and Plummer, 1990). The Cochran’s Q-statistic and I2 test were used to evaluate potential heterogeneity between studies (Biggerstaff and Jackson, 2008). If the Q-test showed a p < 0.05 or the I2 test exhibits > 50%, which indicates significant heterogeneity, the random-effects model was conducted, or else the fixed-effects model was used. We also performed subgroup and meta-regression analyses to explore the potential sources of heterogeneity. Sensitivity analysis was performed by omitting each study in turn to valuate the influence of single studies on the overall estimate.
Quality assessment
We evaluated the methodological quality of the included studies according to the Newcastle-Ottawa Scale (NOS) criteria (Stang, 2010). The NOS criteria included three aspects: (1) subject selection: 0–4 scores; (2) comparability of subject: 0–2 scores; and (3) clinical outcome: 0–3 scores. The NOS score ranged from 0 to 9; and a score ‡ 7 indicates good quality.
FIG. 3. Forest plots for the relationship between pituitary tumor transforming gene (PTTG) expression and tumor invasiveness of pituitary adenomas.
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FIG. 4. Forest plots for the relationship between PTTG expression and microvessel density of pituitary adenomas.
The Begger’s funnel plots and Egger’s linear regression test were conducted to investigate publication bias (Peters et al., 2006). Results Baseline characteristics of included studies
A total of 986 articles relevant to the searched keywords were initially identified. The titles and abstracts of all articles were reviewed and 529 were excluded; full texts and data integrity were then reviewed and another 432 articles were excluded. Finally, 15 clinical cohort studies were included in this meta-analysis (Liu et al., 2004; Wang et al., 2005, 2008; Hu et al., 2006; Li et al., 2006, 2007, 2008; Xiong et al., 2006; He et al., 2008; Zhou and Chen, 2008; Wu et al., 2010; Mo et al., 2011; Shen and Cui, 2012; Zhang et al., 2012; Sun et al., 2013). Publication years of the eligible studies ranged from 2004 to 2013. The selection process of eligible studies is shown in Figure 1. The distribution of the number of topicrelated literatures in the electronic database during the last decade is shown in Figure 2. A total of 752 pituitary adenoma patients, who were Asians, were involved in this meta-analysis, including 405 patients with invasive pituitary adenomas
FIG. 5. Sensitivity analysis of the associations between PTTG expression and biological characteristics of pituitary adenomas. Results were computed by omitting each study in turn. Meta-analysis random-effects estimates (exponential form) were used. The two ends of the dotted lines represent the 95% confidence interval.
and 347 patients with noninvasive pituitary adenomas. There were 170 patients from the experiment in microvessel density analysis, including 112 invasive and 58 noninvasive patients. All the power for the sample size of included studies was higher than 0.60 except two studies (Hu et al., 2006; Li et al., 2008). The classical immunohistochemistry method was performed to detect PTTG protein expression in all included studies. We summarized the study characteristics and methodological quality in Table 1. Quantitative data synthesis
The random-effects model was conducted due to significant heterogeneity that existed between studies. The metaanalysis results showed that patients with invasive pituitary adenomas had a higher positive expression of PTTG than those of noninvasive patients (OR = 6.68, 95% CI = 3.72* 11.99, p < 0.001) (Fig. 3). We also found a significant difference in microvessel density between invasive and noninvasive patients (OR = 1.81, 95% CI = 0.39*3.23, p < 0.001) (Fig. 4). Sensitivity analysis was performed to assess the influence of each individual study on the pooled ORs by omitting each individual study. The analysis results suggested that no
PTTG EXPRESSION AND PITUITARY ADENOMAS
individual studies significantly affected the pooled ORs (Fig. 5), indicating a statistically robust result. The shapes of Begger’s funnel plots did not reveal any evidence of obvious asymmetry (Fig. 6). The Egger’s test also displayed no significant statistical evidence of publication bias (t = - 1.59, p = 0.135). Discussion
Pituitary adenomas arise from epithelial pituitary cells and account for 10–15% of all intracranial tumors (Cuny et al., 2013). With the development of molecular biology and cytogenetic techniques, substantial advances in the understanding of pathogenesis and progression of pituitary tumors have been achieved (Fedele and Fusco, 2013; Jaffrain-Rea and Beckers, 2013; Zhou, 2013). Abundant studies have evaluated the roles of PTTG expression in human pituitary adenomas (McCabe et al., 2003; Hsueh et al., 2013; Zhou et al., 2013). PTTG is an oncogene found in pituitary adenomas, and its encoded proteins are involved in a variety of physiological processes, such as gene activation, cell transformation, angiogenesis, apoptosis, DNA repair, and genetic stability control (Zhang et al., 1999). Tfelt-Hansen et al. (2006) have inferred that PTTG is one of the key factors in the occurrence, proliferation, and invasion of a variety of tumors. Zhang et al. (1999) concluded that the ubiquitous and prevalent expression of pituitary adenoma PTTG suggests that PTTG plays a role in pituitary tumorigenesis and invasiveness. The important role of PTTG prompted researchers to investigate the relationship between PTTG and the biological characteristics of pituitary tumors (Gagliano et al., 2013; Hsueh et al., 2013). Raverot et al. (2010) have also demonstrated that expression of the PTTG was related to invasiveness of prolactin adenomas. In the present meta-analysis, we evaluated the roles of PTTG expression in human pituitary adenomas. Finally, 15 independent cohort studies were included with a total of 752 pituitary adenoma patients. Our meta-analysis results suggested that high expression of PTTG was closely associated with enhanced invasiveness of pituitary adenomas, indicating
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that a high expression level of PTTG was related to the invasiveness of pituitary adenomas. We also observed that the microvessel density in invasive patients was significantly higher compared with noninvasive patients, suggesting that PTTG expression could be an indicator of the tumor proliferative activity and might serve as a potential marker of poor prognosis and tumor recurrence for patients with pituitary adenomas. A study by Filippella et al. (2006) has suggested the association between PTTG and the recurrence of pituitary adenomas in humans, and set the expression level of PTTG more than 3% as the standard for the confirmation of recurrence. These claims are in accordance with our findings in the present meta-analysis. Although the exact function of PTTG in the development and progression of pituitary adenomas is not fully understood yet, a potential explanation might be that high expression of PTTG could cause cell transformation and induce aneuploidy with the abundance of PTTG possibly leading to the dysregulation of G2/M checkpoint surveillance, leading to abnormal mitosis, and leading to chromosomal instability (Yu et al., 2003; Chesnokova et al., 2005; Donangelo et al., 2006; Chesnokova et al., 2007). All in all, our findings were consistent with previous studies that PTTG expression was associated with biological characteristics of human pituitary adenomas and might play important roles in the development of pituitary tumors, suggesting that PTTG expression may be a useful biomarker for pituitary adenomas. This is the first meta-analysis focused on the relationships between PTTG expression and biological characteristics of pituitary tumors. Nevertheless, our meta-analysis also had some limitations. First, our results may not provide sufficient statistical power to estimate the roles of PTTG expression in human pituitary adenomas due to the relatively small sample size. Second, meta-analysis is a retrospective study that may lead to subject selection bias, thereby affecting the reliability of our results. Third, our meta-analysis failed to obtain original data from the included studies, which may limit further evaluation of potential roles of PTTG in pituitary adenoma patients. Importantly, the inclusion criteria of cases and controls were not well defined in all included studies, which might also influence our results. In conclusion, our meta-analysis suggests that PTTG expression may be associated with tumor invasiveness and microvessel density of pituitary adenomas. Thus, detection of PTTG expression may be useful for prediction of malignancy degree in pituitary adenomas. However, due to the limitations mentioned above, further detailed studies are still required to confirm our findings. Acknowledgments
FIG. 6. Begger’s funnel plots of the associations between PTTG expression and biological characteristics of pituitary adenomas. Each point represents a separate study for the indicated association. Log [OR], natural logarithm of odds ratio. Horizontal line, mean magnitude of the effect.
The authors would also like to thank all their colleagues working in the Department of Laboratory Medicine and Molecular Oncology Department of Cancer Research Institution, The First Hospital of China Medical University. This study was supported by a grant from the Science and Technology Research Project of the Higher Education Department of Liaoning Province (No. L2010695). Author Disclosure Statement
The authors have declared that no competing interests exist.
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Address correspondence to: You-Hong Jiang, MD Molecular Oncology Department of Cancer Research Institution The First Hospital of China Medical University Nanjing Street No. 155 Heping District Shenyang 110001 People’s Republic of China E-mail: [email protected]
