J Cancer Res Clin Oncol DOI 10.1007/s00432-014-1844-7
ORIGINAL ARTICLE - CLINICAL ONCOLOGY
The prognostic significance of p53 expression in gastric cancer: a meta-analysis Kongkong Wei · Lei Jiang · Yaoyao Wei · Yufeng Wang · Xuankun Qian · Qiang Dai · Quanlin Guan
Received: 27 May 2014 / Accepted: 26 September 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Objective This meta-analysis was conducted to quantitatively assess the prognostic significance of p53 expression in gastric cancer patients. Methods A systematic literature search was conducted to identify eligible studies in PubMed and Embase. The pooled hazard ratios (HRs) or odds ratios (ORs) with their corresponding 95 % confidence intervals (95 % CIs) were used to estimate the effect sizes. Moreover, meta-regression analysis and subgroup analysis were carried out. Results A total of 34 studies comprising 6,599 patients were subjected to final analysis. Positive/high p53 expression was significantly associated with poorer overall survival (HR 1.56, 95 % CI 1.23–1.98) and disease-specific survival (HR 1.52, 95 % CI 1.35–1.73). The results also indicated that positive/high p53 expression was significantly associated with gender (OR 1.26, 95 % CI 1.09– 1.45), Lauren’s classification (OR 1.68, 95 % CI 1.23– 2.29), the depth of invasion (OR 0.68, 95 % CI 0.56–0.83),
Electronic supplementary material The online version of this article (doi:10.1007/s00432-014-1844-7) contains supplementary material, which is available to authorized users. K. Wei · Y. Wang · X. Qian · Q. Dai The First Clinical Medical College of Lanzhou University, Lanzhou, China L. Jiang · Q. Guan (*) Department of Oncological Surgery, The First Hospital of Lanzhou University, No. 1, Donggang West Road, Cheng Guan District, Lanzhou 730000, Gansu, China e-mail: [email protected] Y. Wei Department of Critical Care Medicine, Jiuquan People’s Hospital, Jiuquan, China
lymph node metastasis (OR 1.56, 95 % CI 1.23–1.97), TNM stage (OR 0.57, 95 % CI 0.47–0.69), vascular invasion (OR 1.51, 95 % CI 1.18–1.92) and lymphatic invasion (OR 1.38, 95 % CI 1.11–1.72), but not with Bormann type (OR 1.24, 95 % CI 0.91–1.70), grade of differentiation (OR 1.08, 95 % CI 0.82–1.44) or distant metastasis (OR 1.37, 95 % CI 0.92–2.03). Conclusions This meta-analysis suggests positive/high p53 expression may be a useful biomarker to predict a poorer prognosis for patients with gastric cancer. Keywords p53 · Gastric cancer · Prognosis · Meta-analysis Abbreviations HR Hazard risk OR Odds ratio CI Confidence interval OS Overall survival DSS Disease-specific survival VEGF Vascular endothelial growth factor COX-2 Cyclooxygenase-2 IHC Immunohistochemistry
Introduction Despite a steady drop in its incidence over the last decades, gastric cancer remains one of the most frequent malignant tumors and the second-leading cause of cancer-related death worldwide (Bertuccio et al. 2009; Jemal et al. 2011). Surgical resection is the only potentially curative treatment for gastric cancer, but its therapeutic effect is limited due to a high incidence of recurrence and metastasis even after radical surgery (Yoo et al. 2000). The exceptions are Japan
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and Korea, where early detection is more common than in other regions of the world, and approximately 50 % of patients were diagnosed at an early stage of gastric cancer (Inoue and Tsugane 2005; Kim et al. 2011). The prognosis of gastric cancer is still poor with an overall 5-year survival rate of 10 %
NR
NR
Median 46.0 (range 0.6–62.2)
NR
NR Mean 120 NR
>15 %
62.0
77.6
>10 %
Mean 43 (range 2–191)
Median 54.8
62.8
20.0
>10 %
43.3
41.0
57.7
45.5
86.8
61.9
65.6
63.7 49.3
44.7
48.0
83.3
63.4
59.7
At least 60
34.8
>10 %
59.4
4 years
27.9
63.8
51.7
NR
73.2
Quality Score (%)
53.7
Positive/ high (%)
Median 20 (range 1–155)
Median 34 >10 % (range 2–83.5) Mean 33.7 ≥5 % (range 1–132)
Follow-up (months)
OS
DSS
OS OS
OS
OS
DSS
OS
OS
OS
DSS
OS, DSS
OS
DSS
Outcome
HR
Indirect
Indirect Indirect
Indirect
Indirect
Indirect
Indirect
HR
Indirect
HR
HR
HR
HR
HR extraction
M
U
M U
U
U
U
U
M
U
M
U
U
M
Analytic method
J Cancer Res Clin Oncol
13
13
105
494
Korea
Japan
China
Song et al. (2009)
Tsujitani et al. (2012) Xiao et al. (2013)
136
China
Japan Korea
Ide et al. (2012) Joo et al. (2002)
192 145
126
Italy
Matturri et al. (1998) Zha et al. (2012)
157
96
Italy
78
Slovenia
Sgambato et al. (2000)
I–IV
75
Brazil
210
I–IV
Portugal 163
Pinto-de-Sousa et al. (2004) Lehrbach et al. (2009) Potrc et al. (2007)
Japan
I–IV
190
Japan
Liu et al. (2001)
Sawada et al. (2014)
I–IV
374
I–IV I–IV
I–III
III
0–IV
NR
III
NR
II–III
I–IV
NR
116
I–IV
Stage
Australia Liu et al. (2012a, b) China
Lim et al. (1996)
China
Lee et al. (1998)
168
Country Patient number
Author
Table 1 continued
Patients with curative resection for gastric cancer received adjuvant paclitaxel plus capecitabine chemotherapy Patients underwent surgical resection Patients underwent curative surgery for gastric cancer. No patient had received anticancer therapy prior to the operation
Patients underwent potentially curative resection (R0) All of patients underwent curative R0 resection by gastrectomy with more than D1 lymph node dissection All of the patients underwent surgery with curative intent, and none of them had received any therapy before surgery Patients underwent potentially curative resection, and none of them received any form of treatment prior to surgery All patients underwent postoperative chemotherapy after curative gastrectomy Patients underwent curative resection. None underwent chemotherapy, radiotherapy and adjuvant treatment prior to surgery Patients underwent gastrectomy
Patients had undergone gastric resection for primary gastric adenocarcinoma. No patients had undergone previous chemotherapy or radiotherapy Patients underwent surgery for gastric carcinoma Patients were treated with surgery only or with postoperative adjuvant chemotherapy Patients underwent curative gastrectomy. None of patients received chemo- or radiotherapy Patients underwent surgical resection for gastric carcinoma Patients underwent surgical resection
Treatment
9.4
Mean 52 (range: >30 % 4–120)
39.1 35.9
64.7
Score 3
>10 % Staining index > 4
17.5
52.8
Score 1 Mean 70.1 (range 0.2–146.4) Mean 48 (range 36–72) Median 58 (range 13.8–72.0) NR NR
≥20 %
63.8
>10 %
At least 60
54.8
41.4
Score 2
NR
≥10 %
46.2
1–25 %
NR
68.0
25.2
42.1
Score 2
>5 %
≥20 %
38.0
61.5 55.7
60.7
50.4
64.0
57.7
56.6
75.0
54.7
55.5
57.1
59.7
58.1
73.7
60.6
52.2
20.2
23.3
Quality Score (%)
Positive/ high (%)
Mean 60 (range 4–273) Median 81.7
NR
At least 48
Score 4
A strong coloration of the cell nucleus ≥5 %
Median 48
Mean 41 (range 1–166) NR
Cutoff
Follow-up (months)
DSS DSS
OS
OS
OS
OS
OS
DSS
OS
OS
OS
OS
DSS
OS
DSS
OS
Outcome
Indirect Indirect
Indirect
Indirect
HR
Indirect
HR
HR
Indirect
Indirect
Indirect
Indirect
HR
HR
Indirect
Indirect
HR extraction
M U
U
U
M
U
M
M
U
U
U
U
M
M
U
U
Analytic method
J Cancer Res Clin Oncol
Analytic method
U
M
U
U
HR
HR
Indirect
Indirect DSS 68.4
OS overall survival, DSS disease-specific survival, HR hazard ratio, U univariate, M multivariate, NR not reported
65.4 Median 20 (range ≥10 % Patients underwent potentially curative gastrectomy with D1 lymph node dissection. 3–75) None of the patients had received chemotherapy or radiotherapy before surgery I–IV Greece Zafirellis et al. (2005)
52
DSS 55.9 83 Italy Roviello et al. (1999)
I–IV 336
I–IV
51.8
DSS 56.0 31.0
≥20 % Median 152.4 156 of 336 patients underwent curative (range 56.4– surgery, and the remaining patients received 249.6) palliative surgery Mean 101 (range ≥10 % Patients had undergone exeresis for primary 42–140) gastric cancer. None of the patients received adjuvant chemotherapy or radiotherapy
DSS 58.5 38.6 ≥10 % NR Patients underwent gastric resection I–IV
Maehara et al. Japan (1999) Mrena et al. (2010) Finland
427
Follow-up (months) Stage Country Patient number Author
Table 1 continued
we excluded any single study at a time and evaluated the rest. The results indicated that none of the included studies had a significant influence on the pooled HR, ranging from 1.38 (95 % CI: 1.21–1.57) after excluding the study of Liu et al. (2012b) to 1.61 (95 % CI 1.27–2.05) after excluding the study of Kasper et al. (1999). p53 expression and DSS
Treatment
Cutoff
Positive/ high (%)
Quality Score (%)
Outcome
HR extraction
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A total of 14 studies including 2,128 patients were used to assess the association of positive/high p53 expression with DSS in gastric cancer patients (Fig. 3). Positive/high p53 expression was statistically significant association with poorer DSS in patients with gastric cancer (fixed effects: HR 1.52; 95 % CI 1.35–1.73; P = 0.103 for heterogeneity, I2 = 34 %). In addition, a statically significant effect of positive/high p53 expression on DSS was also observed in the subgroup with Asian patients (fixed effects: HR, 1.47; 95 % CI, 1.32–1.71; P = 0.179 for heterogeneity, I2 = 34.3 %) and non-Asian patients (fixed effects: HR 1.64; 95 % CI 1.32–2.04; P = 0.121 for heterogeneity, I2 = 38.8 %), which suggested that there was no significant ethnical discrepancy in the estimates of the effect of p53 expression on DSS between Asians and non-Asians. The same effect of positive/high p53 expression on DSS was observed either in the univariate subgroup (fixed effects: HR 1.47; 95 % CI 1.26–1.71; P = 0.193 for heterogeneity, I2 = 29.5 %) or in the multivariate subgroup (fixed effects: HR 1.64; 95 % CI 1.32–2.03; P = 0.106 for heterogeneity, I2 = 45.0 %). p53 expression and clinicopathological features We also evaluated the association between p53 expression and clinicopathological features of gastric cancer (Table 4). Positive/high p53 expression was statistically significant association with gender (male vs. female: OR 1.26, 95 % CI 1.09–1.45), Lauren’s classification (intestinal type vs. diffuse type: OR 1.68, 95 % CI 1.23–2.29), the depth of invasion (T1/T2 vs. T3/T4: OR 0.68, 95 % CI 0.56–0.83), lymph node metastasis (positive vs. negative: OR 1.56, 95 % CI 1.23–1.97), TNM stage (I/II vs. III/IV: OR 0.57, 95 % CI 0.47–0.69), vascular invasion (positive vs. negative: OR 1.51, 95 % CI 1.18–1.92) and lymphatic invasion (positive vs. negative: OR 1.38, 95 % CI 1.11–1.72), but not with Bormann type (I/II vs. III/IV: OR 1.24, 95 % CI 0.91–1.70), grade of differentiation (1/2 vs. 3/4: OR 1.08, 95 % CI 0.82–1.44) or distant metastasis (positive vs. negative: OR 1.37, 95 % CI 0.92–2.03). Furthermore, no significant heterogeneity between studies was observed in the meta-analysis of the correlation between p53 expression and all clinicopathological features (I2 ranging 0.0–34.7 %) except for Lauren’s classification (I = 67.7 %, P = 0.000) and lymph node metastasis (I2 = 43.9 %, P = 0.021).
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Table 2 Results of the methodological assessment of included studies No. of studies
Designa
Methoda
Generalizabilitya
Results analysisa
Global score (%)
All studies Direct extraction Indirect extraction
34 12 22
P value Asian Non-Asian
5 5.5 5 0.423
6.4 7.2 6.4 0.191
6.7 6.7 6.7 0.736
6.3 6.9 5 0.000
59.7 62.9 58.1 0.017
16 18
4.5 6
6.4 6.4
6.7 6.7
6.3 6.3
59.6 59.7
0.198
0.932
0.646
0.878
P value
0.959
Score distributions are summarized by the median values HR hazard ratio a
Score out of 10
Fig. 2 Forest plot of the overall pooled analysis for the association of p53 expression with OS
Publication bias
Discussion
Both Begg’s funnel plot and Egger’s test were used for assessment of publication bias in the meta-analysis. The shapes of funnel plots did not exhibit obvious asymmetry except for a certain degree asymmetry of studies with the analysis of depth of invasion (Figs. 4, 5). Egger’s test also indicated that there was no significant publication bias (P > 0.05) among studies with overall analysis of OS (P = 0.421), subgroup analysis of OS (P ranging 0.299– 0.691), DSS (P = 0.838) and histopathological features (P ranging 0.115–0.984) except depth of invasion (P = 0.041).
Gastric cancer remains a major health problem due to the slow decline in incidence in Asia and the high mortality in the West, despite advanced diagnostic and operative techniques widely used in clinical practice (Kelley and Duggan 2003; Rivera et al. 2007). The prognosis of gastric cancer varies but is still poor mainly resulting from a high incidence of metastasis and recurrence (Anderson et al. 2006). The TNM staging system for gastric cancer is universally applied in clinical decision-making to provide relevant prognostic information (Huang et al. 2001), but alone, it is
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J Cancer Res Clin Oncol Table 3 Summarized HRs of overall and subgroup analyses for OS in gastric cancer patients with p53 expression
No. of studies
Overall Ethnicity Asian Non-Asian HR extraction Direct Indirect Sur. analysis Univariate Multivariate Quality score (%) 60
Random effects HR (95 % CI)
Heterogeneity I (%)
P value
21
1.56 (1.23–1.98)
85.7
0.000
10 11
1.64 (1.06–2.54) 1.46 (1.21–1.76)
92.7 38.3
0.000 0.094
7 14
1.98 (1.14–3.45) 1.36 (1.16–1.59)
94.9 29.7
0.000 0.140
15 6
1.41 (1.19–1.68) 1.84 (1.01–3.34)
43.0 95.6
0.039 0.000
2
Meta-regression P value
Egger’s test
0.421 0.682 0.553 0.426 0.139 0.340 0.574 0.326 0.299 0.450 0.249
11
1.36 (1.15–1.61)
24.4
0.211
0.691
10
1.80 (1.17–2.76)
92.8
0.000
0.375
Fig. 3 Forest plot of the association of p53 expression with DSS
not adequately accurate. Gastric cancer progression is now considered to be a multistep process implicating growthpromoting and anti-apoptotic signals (Kountouras et al. 2005). Therefore, biological markers may be additionally useful predictors of prognosis for gastric cancer. p53 tumor-suppressor gene and its coded protein play a key role in the signaling of cell cycle arrest and apoptosis. Most mutations in the p53 gene are missense and result in accumulation of p53 in the nucleus. Therefore, p53
over-expression is generally associated with inactivation of p53 (Cordon-Cardo et al. 1994). Based on its functions, positive/high p53 expression in cancer cells may increase proliferative activity of cells, allowing the development and progression of tumor cells and finally leading to a poor prognosis. However, mutations of p53 do not necessarily mean the accumulation of p53 detected by IHC. Gene abnormalities other than missense mutations do not result in accumulations of nuclear protein and therefore escape
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J Cancer Res Clin Oncol
Table 4 Meta-analysis of p53 expression and clinicopathological features of gastric cancer Clinicopathological features
Gender (male vs. female) Bormann type (I/II vs. III/IV) Grade of differentiation (1/2 vs. 3/4) Lauren’s classification (intestinal type vs. diffuse type) Depth of invasion (T1/T2 vs. T3/T4) Lymph node metastasis (P vs. N) Distant metastasis (P vs. N) TNM stage (I/II vs. III/IV) Vascular invasion (P vs. N) Lymphatic invasion (P vs. N)
N
Cases
Analytical model
Pooled OR (95 % CI)
P value
Heterogeneity 2
I (%)
P value
Egger’s test
17 3 6 18
3,830 921 1,078 3,219
FEM FEM FEM REM
1.26 (1.09–1.45) 1.24 (0.91–1.70) 1.08 (0.82–1.44) 1.68 (1.23–2.29)
0.002 0.174 0.572 0.001
0.0 0.0 33.8 67.7
0.943 0.849 0.183 0.000
0.611 0.152 0.115 0.738
17 19 10 12 7
2,566 3,194 1,347 2,221 1,655
FEM REM FEM FEM FEM
0.68 (0.56–0.83) 1.56 (1.23–1.97) 1.37 (0.92–2.03) 0.57 (0.47–0.69) 1.51 (1.18–1.92)
0.000 0.000 0.122 0.000 0.001
7.1 43.9 0.0 34.7 0.0
0.371 0.021 0.456 0.113 0.445
0.041 0.475 0.233 0.957 0.979
5
1,430
FEM
1.38 (1.11–1.72)
0.004
10.6
0.346
0.984
N number of studies, P positive, N negative, REM random-effects model, FEM fixed-effects model, OR odds ratio, CI confidence interval
Fig. 4 Funnel plot of the overall pooled analysis for the association of p53 expression with OS
Fig. 5 Funnel plot of the overall pooled analysis for the association of p53 expression with DSS
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detection by IHC. Some missense mutations lead to a stop codon and may yield a truncated protein that is not detectable by IHC (Fenoglio-Preiser et al. 2003). In addition, there are numerous regulatory mechanisms which modulate p53 activity positively or negatively. For example, some products of the MDM2 oncogene and of viral genes may render p53 unstable and lead to p53 low/negative expression (Li et al. 2004). A physiological response to damaged DNA may lead to over-expression of p53 (Soussi 2000). So far, numerous studies investigated the correlation between p53 expression and the prognosis of gastric cancer but yielded controversial results. To our knowledge, this is the first meta-analysis to quantitatively assess the association between p53 expression and survival as well as clinicopathological features in gastric cancer. In the present meta-analysis, a total of 34 studies comprising 6,599 cases were subjected to final analysis. In the overall pooled analysis of the association of p53 expression with survival in gastric cancer patients, the results suggested that positive/high p53 expression was statistically significantly related to poorer OS (HR 1.56, 95 % CI 1.23–1.98) and DSS (HR 1.52, 95 % CI 1.35–1.73). These findings demonstrated the significance of p53 expression in the prognosis of patients with gastric cancer and were in accordance with theoretical inference that patients with positive/high p53 expression could have a worse clinical prognosis than those with negative/low p53 expression. The same results have been reported in the meta-analyses of other carcinomas, such as hepatocellular carcinoma (Liu et al. 2012a), extrahepatic bile duct carcinoma (Wang et al. 2011), bladder carcinoma (Malats et al. 2005), upper urinary tract urothelial carcinoma (Ku et al. 2013), osteosarcoma (Fu et al. 2013; Pakos et al. 2004), lung carcinoma (Steels et al. 2001) and esophageal carcinoma (Chen et
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al. 2013). In the current study, a significant correlation of positive/high p53 expression with OS (P = 0.045) as well as DSS (P = 0.000) was observed in the multivariate subgroup, which suggested that p53 expression may be an independent prognostic indicator of poorer survival, but it should be noted that a significant heterogeneity was presented among the studies with multivariate analysis of OS (I2 = 95.6 %, P = 0.000). In subgroup analysis of OS and DSS according to ethnicity, there was no evidence for ethnical discrepancy in the estimates of the impact of p53 expression on survival between Asians and non-Asians. In addition, nine studies (Bataille et al. 2003; De Dosso et al. 2013; Kubicka et al. 2002; Lim et al. 1996; Migliavacca et al. 2004; Mrozek et al. 2003; Ott et al. 2003; PuhringerOppermann et al. 2006; Solcia et al. 2009) were included to quantitatively assess the association between p53 mutations and survival in patients with gastric cancer (Table S1). p53 mutations were significantly correlated with poorer DSS (fixed effects: HR 1.70, 95 % CI 1.29–2.24; P = 0.189 for heterogeneity, I2 = 42.0 % Fig. S1) but not OS (random effects: HR 1.65, 95 % CI 0.85–3.19; P = 0.001 for heterogeneity, I2 = 72.7 % Fig. S2). However, we found that studies reporting the association between p53 mutations and OS had a small number of cases and significant between-study heterogeneity, which mainly resulted from Bataille et al. (2003). When Bataille et al. (Bataille et al. 2003) was excluded, we reanalyzed the remaining data and observed a significant association between p53 mutations and poorer OS (random effects: HR = 2.08, 95 % CI 1.16– 3.75; P = 0.033 for heterogeneity, I2 = 58.8 %). We also assessed the associations between p53 expression and clinicopathological features; positive/high p53 expression was significantly associated with some of clinicopathological features, such as gender, Lauren’s classification, the depth of invasion, lymph node metastasis, TNM stage, vascular invasion and lymphatic invasion, but not with Bormann type, grade of differentiation and distant metastasis. According to Lauren’s classification (Lauren 1965), gastric cancer is divided into intestinal type and diffuse type. It has been demonstrated that these two histological types have some differences in epidemiology, pathogenesis and clinical outcome (Roder 2002). In this study, we observed that p53 expression was higher in intestinal type compared with diffuse-type gastric cancer, which may be due to the existence of a distinct carcinogenetic pathway between the two histological types of gastric cancer (Zafirellis et al. 2005). Moreover, there were significant relationships between positive/high p53 expression and adverse prognostic features such as a higher incidence of vascular and lymphatic invasion, deeper wall invasion, increased lymph node metastases and a more advanced TNM stage, which may conduce to the understanding of how positive/high p53 expression is correlated with a more
aggressive biological behavior of gastric cancer (Pinto-deSousa et al. 2004) and why positive/high p53 expression is associated with a poorer prognosis in patients with gastric cancer. However, no significant associations between p53 expression and Bormann type, grade of differentiation and distant metastasis were observed in the study; the results may be due to the small sample sizes of studies included in the analysis and need to be further confirmed by the larger sample sizes. In the test of heterogeneity, there was a significant heterogeneity in the analysis of the association of p53 expression with OS in gastric cancer. Although the data were aggregated using the random-effects models, heterogeneity among the studies continued to be a potential problem to influence the reliability of pooled results. Hence, we carried out meta-regression and subgroup analysis according to ethnicity, HR extraction, survival analysis and quality score. However, none of these factors was found to be significantly correlated to heterogeneity using meta-regression analysis, and subgroup analysis still exhibited significant heterogeneity among the studies. The heterogeneity probably results from differences in the baseline characteristics of patients, immunohistochemical methods, the establishment of positive/high p53 expression, the treatments to the patients, the duration of follow-up or others among included studies. Unfortunately, we could not use the available information to further identify the sources of heterogeneity. To verify the stability of the combined results in the meta-analysis, sensitivity analysis was conducted. The combined HRs were not significantly influenced by excluding any individual study and then reanalyzing the remaining data. It should be noted that our meta-analysis has several limitations. Firstly, to reduce the bias from different detection methods, we only included the studies measuring p53 expression by IHC in the meta-analysis. IHC has been widely applied to detect molecular markers of cancer, because the method is simple and fast and agrees with other methodologies (Lee et al. 2003a). However, the differences of the types of antibody, concentration and cutoff value used in IHC might produce potential bias. It is, therefore, necessary to define a standardized protocol and evaluation system to promote the application of molecular markers detected by IHC in clinical practice. Secondly, the variation of methodological quantity among included studies could be a source of bias. The method reported by Steels et al. (Steels et al. 2001) was used as the criteria of quantity assessment in the meta-analysis. Although a significant correlation of p53 expression with OS was observed in two subgroups stratified by quality score, the bias should not be ignored. Thirdly, the approach of HR extraction might result in bias. If HRs with 95 % CIs were not directly reported in the literatures, they had to
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be obtained indirectly from the relevant data or survival curves presented in the articles. In the study, quality scores between the two approaches of HR extraction did exhibit statistically significant deviation. Fourthly, publication bias is a common concern for all meta-analyses (Begg 1988), although no publication bias was found in all relevant analysis except in the analysis of the correlation between p53 expression and depth of invasion. Moreover, the studies included in the meta-analysis were restricted to full publications in English language and could exclude other potentially eligible studies, which also probably resulted in bias. Finally, all of included studies were observational trials, which contained the greater potential confounders and provided the lower level of evidence compared with randomized controlled studies. Therefore, the results should be interpreted cautiously. Despite these limitations, the present study is the first meta-analysis to quantitatively assess the association between p53 expression and survival as well as clinicopathological features in gastric cancer. We concluded that high/positive p53 expression was significantly associated with poorer survival and some adverse clinicopathological features. p53 over-expression may be a useful biomarker to predict a poorer prognosis for gastric cancer patients and to identify a subgroup of patients who may benefit from personalized treatment. However, to strengthen our findings, further larger prospective studies with better standardized methods are needed to make a comprehensive conclusion on the prognostic role of p53 expression in gastric cancer. Acknowledgments This study was supported by the Fundamental Research Funds for the Central Universities (Number: lzujbky-2013-160). Conflict of interest All the authors indicated no potential conflicts of interest.
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Liu X et al (2012b) Synergistic role between p53 and JWA: prognostic and predictive biomarkers in gastric cancer. PLoS ONE 7:e52348 Maehara Y, Tomoda M, Hasuda S, Kabashima A, Tokunaga E, Kakeji Y, Sugimachi K (1999) Prognostic value of p53 protein expression for patients with gastric cancer: a multivariate analysis. Br J Cancer 79:1255–1261 Malats N et al (2005) P53 as a prognostic marker for bladder cancer: a meta-analysis and review. Lancet Oncol 6:678–686 Matturri L et al (1998) Prognostic significance of different biological markers (DNA index, PCNA index, apoptosis, p53, karyotype) in 126 adenocarcinoma gastric biopsies. Anticancer Res 18:2819–2825 Migliavacca M et al (2004) TP53 in gastric cancer: mutations in the l3 loop and LSH motif DNA-binding domains of TP53 predict poor outcome. J Cell Physiol 200:476–485 Mrena J, Wiksten JP, Kokkola A, Nordling S, Ristimaki A, Haglund C (2010) COX-2 is associated with proliferation and apoptosis markers and serves as an independent prognostic factor in gastric cancer. Tumour Biol 31:1–7 Mrozek A et al (2003) Combined p53/Bax mutation results in extremely poor prognosis in gastric carcinoma with low microsatellite instability. Cell Death Differ 10:461–467 Muller PA, Vousden KH, Norman JC (2011) p53 and its mutants in tumor cell migration and invasion. J Cell Biol 192:209–218 Ott K et al (2003) Chromosomal instability rather than p53 mutation is associated with response to neoadjuvant cisplatin-based chemotherapy in gastric carcinoma. Clin Cancer Res 9:2307–2315 Pakos EE, Kyzas PA, Ioannidis JP (2004) Prognostic significance of TP53 tumor suppressor gene expression and mutations in human osteosarcoma a meta-analysis. Clin Cancer Res 10:6208–6214 Parmar MK, Torri V, Stewart L (1998) Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med 17:2815–2834 Peng L, Zhan P, Zhou Y, Fang W, Zhao P, Zheng Y, Xu N (2012) Prognostic significance of vascular endothelial growth factor immunohistochemical expression in gastric cancer: a meta-analysis. Mol Biol Rep 39:9473–9484 Pinto-de-Sousa J, Silva F, David L, Leitao D, Seixas M, Pimenta A, Cardoso-de-Oliveira M (2004) Clinicopathological significance and survival influence of p53 protein expression in gastric carcinoma. Histopathology 44:323–331 Potrc S, Gadiijev E, Hajdinjak T, Kavalar R (2007) Clinicopathological and immunohistochemical markers after radical gastrectomy for gastric cancer. Hepatogastroenterology 54:308–314 Puhringer-Oppermann F, Stahl M, Keller G, Sarbia M (2006) Lack of prognostic impact of p53 gene mutation and p53 phosphorylation at serine 15 in multimodally treated adenocarcinomas of the gastroesophageal junction. J Cancer Res Clin Oncol 132:433–438 Rivera F, Vega-Villegas ME, López-Brea MF (2007) Chemotherapy of advanced gastric cancer. Cancer Treat Rev 33:315–324 Roder DM (2002) The epidemiology of gastric cancer. Gastric Cancer 5:5–11 Roviello F, Marrelli D, Vindigni C, De Stefano A, Spina D, Pinto E (1999) P53 accumulation is a prognostic factor in intestinal-type gastric carcinoma but not in the diffuse type. Ann Surg Oncol 6:739–745 Sawada T et al (2014) New molecular staging with G-factor supplements TNM classification in gastric cancer: a multicenter collaborative research by the Japan society for gastroenterological carcinogenesis G-project committee. Gastric Cancer. doi:10.1007/ s10120-014-0338-2 Sgambato A et al (2000) Loss of p27Kip1 expression is a strong independent prognostic factor of reduced survival in N0 gastric carcinomas. Cancer 89:2247–2257
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Siegel R, Ma J, Zou Z, Jemal A (2014) Cancer statistics, 2014. CA Cancer J Clin 64:9–29 Solcia E et al (2009) A combined histologic and molecular approach identifies three groups of gastric cancer with different prognosis. Virchows Arch 455:197–211 Song KY, Jung CK, Park WS, Park CH (2009) Expression of the antiapoptosis gene survivin predicts poor prognosis of stage III gastric adenocarcinoma. Jpn J Clin Oncol 39:290–296 Song J, Su H, Y-y Zhou, L-l Guo (2013) Cyclooxygenase-2 expression is associated with poor overall survival of patients with gastric cancer: a meta-analysis. Dig Dis Sci 59:436–445 Soussi T (2000) The p53 tumor suppressor gene: from molecular biology to clinical investigation. Ann NY Acad Sci 910:121–137 Soussi T (2005) The p53 pathway and human cancer. Br J Surg 92:1331–1332. doi:10.1002/bjs.5177 Steels E et al (2001) Role of p53 as a prognostic factor for survival in lung cancer: a systematic review of the literature with a metaanalysis. Eur Respir J 18:705–719 Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR (2007) Practical methods for incorporating summary time-to-event data into meta-analysis. Trials 8:16 Toledo F, Wahl GM (2006) Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nat Rev Cancer 6:909–923
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ORIGINAL ARTICLE - CLINICAL ONCOLOGY
The prognostic significance of p53 expression in gastric cancer: a meta-analysis Kongkong Wei · Lei Jiang · Yaoyao Wei · Yufeng Wang · Xuankun Qian · Qiang Dai · Quanlin Guan
Received: 27 May 2014 / Accepted: 26 September 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Objective This meta-analysis was conducted to quantitatively assess the prognostic significance of p53 expression in gastric cancer patients. Methods A systematic literature search was conducted to identify eligible studies in PubMed and Embase. The pooled hazard ratios (HRs) or odds ratios (ORs) with their corresponding 95 % confidence intervals (95 % CIs) were used to estimate the effect sizes. Moreover, meta-regression analysis and subgroup analysis were carried out. Results A total of 34 studies comprising 6,599 patients were subjected to final analysis. Positive/high p53 expression was significantly associated with poorer overall survival (HR 1.56, 95 % CI 1.23–1.98) and disease-specific survival (HR 1.52, 95 % CI 1.35–1.73). The results also indicated that positive/high p53 expression was significantly associated with gender (OR 1.26, 95 % CI 1.09– 1.45), Lauren’s classification (OR 1.68, 95 % CI 1.23– 2.29), the depth of invasion (OR 0.68, 95 % CI 0.56–0.83),
Electronic supplementary material The online version of this article (doi:10.1007/s00432-014-1844-7) contains supplementary material, which is available to authorized users. K. Wei · Y. Wang · X. Qian · Q. Dai The First Clinical Medical College of Lanzhou University, Lanzhou, China L. Jiang · Q. Guan (*) Department of Oncological Surgery, The First Hospital of Lanzhou University, No. 1, Donggang West Road, Cheng Guan District, Lanzhou 730000, Gansu, China e-mail: [email protected] Y. Wei Department of Critical Care Medicine, Jiuquan People’s Hospital, Jiuquan, China
lymph node metastasis (OR 1.56, 95 % CI 1.23–1.97), TNM stage (OR 0.57, 95 % CI 0.47–0.69), vascular invasion (OR 1.51, 95 % CI 1.18–1.92) and lymphatic invasion (OR 1.38, 95 % CI 1.11–1.72), but not with Bormann type (OR 1.24, 95 % CI 0.91–1.70), grade of differentiation (OR 1.08, 95 % CI 0.82–1.44) or distant metastasis (OR 1.37, 95 % CI 0.92–2.03). Conclusions This meta-analysis suggests positive/high p53 expression may be a useful biomarker to predict a poorer prognosis for patients with gastric cancer. Keywords p53 · Gastric cancer · Prognosis · Meta-analysis Abbreviations HR Hazard risk OR Odds ratio CI Confidence interval OS Overall survival DSS Disease-specific survival VEGF Vascular endothelial growth factor COX-2 Cyclooxygenase-2 IHC Immunohistochemistry
Introduction Despite a steady drop in its incidence over the last decades, gastric cancer remains one of the most frequent malignant tumors and the second-leading cause of cancer-related death worldwide (Bertuccio et al. 2009; Jemal et al. 2011). Surgical resection is the only potentially curative treatment for gastric cancer, but its therapeutic effect is limited due to a high incidence of recurrence and metastasis even after radical surgery (Yoo et al. 2000). The exceptions are Japan
13
and Korea, where early detection is more common than in other regions of the world, and approximately 50 % of patients were diagnosed at an early stage of gastric cancer (Inoue and Tsugane 2005; Kim et al. 2011). The prognosis of gastric cancer is still poor with an overall 5-year survival rate of 10 %
NR
NR
Median 46.0 (range 0.6–62.2)
NR
NR Mean 120 NR
>15 %
62.0
77.6
>10 %
Mean 43 (range 2–191)
Median 54.8
62.8
20.0
>10 %
43.3
41.0
57.7
45.5
86.8
61.9
65.6
63.7 49.3
44.7
48.0
83.3
63.4
59.7
At least 60
34.8
>10 %
59.4
4 years
27.9
63.8
51.7
NR
73.2
Quality Score (%)
53.7
Positive/ high (%)
Median 20 (range 1–155)
Median 34 >10 % (range 2–83.5) Mean 33.7 ≥5 % (range 1–132)
Follow-up (months)
OS
DSS
OS OS
OS
OS
DSS
OS
OS
OS
DSS
OS, DSS
OS
DSS
Outcome
HR
Indirect
Indirect Indirect
Indirect
Indirect
Indirect
Indirect
HR
Indirect
HR
HR
HR
HR
HR extraction
M
U
M U
U
U
U
U
M
U
M
U
U
M
Analytic method
J Cancer Res Clin Oncol
13
13
105
494
Korea
Japan
China
Song et al. (2009)
Tsujitani et al. (2012) Xiao et al. (2013)
136
China
Japan Korea
Ide et al. (2012) Joo et al. (2002)
192 145
126
Italy
Matturri et al. (1998) Zha et al. (2012)
157
96
Italy
78
Slovenia
Sgambato et al. (2000)
I–IV
75
Brazil
210
I–IV
Portugal 163
Pinto-de-Sousa et al. (2004) Lehrbach et al. (2009) Potrc et al. (2007)
Japan
I–IV
190
Japan
Liu et al. (2001)
Sawada et al. (2014)
I–IV
374
I–IV I–IV
I–III
III
0–IV
NR
III
NR
II–III
I–IV
NR
116
I–IV
Stage
Australia Liu et al. (2012a, b) China
Lim et al. (1996)
China
Lee et al. (1998)
168
Country Patient number
Author
Table 1 continued
Patients with curative resection for gastric cancer received adjuvant paclitaxel plus capecitabine chemotherapy Patients underwent surgical resection Patients underwent curative surgery for gastric cancer. No patient had received anticancer therapy prior to the operation
Patients underwent potentially curative resection (R0) All of patients underwent curative R0 resection by gastrectomy with more than D1 lymph node dissection All of the patients underwent surgery with curative intent, and none of them had received any therapy before surgery Patients underwent potentially curative resection, and none of them received any form of treatment prior to surgery All patients underwent postoperative chemotherapy after curative gastrectomy Patients underwent curative resection. None underwent chemotherapy, radiotherapy and adjuvant treatment prior to surgery Patients underwent gastrectomy
Patients had undergone gastric resection for primary gastric adenocarcinoma. No patients had undergone previous chemotherapy or radiotherapy Patients underwent surgery for gastric carcinoma Patients were treated with surgery only or with postoperative adjuvant chemotherapy Patients underwent curative gastrectomy. None of patients received chemo- or radiotherapy Patients underwent surgical resection for gastric carcinoma Patients underwent surgical resection
Treatment
9.4
Mean 52 (range: >30 % 4–120)
39.1 35.9
64.7
Score 3
>10 % Staining index > 4
17.5
52.8
Score 1 Mean 70.1 (range 0.2–146.4) Mean 48 (range 36–72) Median 58 (range 13.8–72.0) NR NR
≥20 %
63.8
>10 %
At least 60
54.8
41.4
Score 2
NR
≥10 %
46.2
1–25 %
NR
68.0
25.2
42.1
Score 2
>5 %
≥20 %
38.0
61.5 55.7
60.7
50.4
64.0
57.7
56.6
75.0
54.7
55.5
57.1
59.7
58.1
73.7
60.6
52.2
20.2
23.3
Quality Score (%)
Positive/ high (%)
Mean 60 (range 4–273) Median 81.7
NR
At least 48
Score 4
A strong coloration of the cell nucleus ≥5 %
Median 48
Mean 41 (range 1–166) NR
Cutoff
Follow-up (months)
DSS DSS
OS
OS
OS
OS
OS
DSS
OS
OS
OS
OS
DSS
OS
DSS
OS
Outcome
Indirect Indirect
Indirect
Indirect
HR
Indirect
HR
HR
Indirect
Indirect
Indirect
Indirect
HR
HR
Indirect
Indirect
HR extraction
M U
U
U
M
U
M
M
U
U
U
U
M
M
U
U
Analytic method
J Cancer Res Clin Oncol
Analytic method
U
M
U
U
HR
HR
Indirect
Indirect DSS 68.4
OS overall survival, DSS disease-specific survival, HR hazard ratio, U univariate, M multivariate, NR not reported
65.4 Median 20 (range ≥10 % Patients underwent potentially curative gastrectomy with D1 lymph node dissection. 3–75) None of the patients had received chemotherapy or radiotherapy before surgery I–IV Greece Zafirellis et al. (2005)
52
DSS 55.9 83 Italy Roviello et al. (1999)
I–IV 336
I–IV
51.8
DSS 56.0 31.0
≥20 % Median 152.4 156 of 336 patients underwent curative (range 56.4– surgery, and the remaining patients received 249.6) palliative surgery Mean 101 (range ≥10 % Patients had undergone exeresis for primary 42–140) gastric cancer. None of the patients received adjuvant chemotherapy or radiotherapy
DSS 58.5 38.6 ≥10 % NR Patients underwent gastric resection I–IV
Maehara et al. Japan (1999) Mrena et al. (2010) Finland
427
Follow-up (months) Stage Country Patient number Author
Table 1 continued
we excluded any single study at a time and evaluated the rest. The results indicated that none of the included studies had a significant influence on the pooled HR, ranging from 1.38 (95 % CI: 1.21–1.57) after excluding the study of Liu et al. (2012b) to 1.61 (95 % CI 1.27–2.05) after excluding the study of Kasper et al. (1999). p53 expression and DSS
Treatment
Cutoff
Positive/ high (%)
Quality Score (%)
Outcome
HR extraction
J Cancer Res Clin Oncol
A total of 14 studies including 2,128 patients were used to assess the association of positive/high p53 expression with DSS in gastric cancer patients (Fig. 3). Positive/high p53 expression was statistically significant association with poorer DSS in patients with gastric cancer (fixed effects: HR 1.52; 95 % CI 1.35–1.73; P = 0.103 for heterogeneity, I2 = 34 %). In addition, a statically significant effect of positive/high p53 expression on DSS was also observed in the subgroup with Asian patients (fixed effects: HR, 1.47; 95 % CI, 1.32–1.71; P = 0.179 for heterogeneity, I2 = 34.3 %) and non-Asian patients (fixed effects: HR 1.64; 95 % CI 1.32–2.04; P = 0.121 for heterogeneity, I2 = 38.8 %), which suggested that there was no significant ethnical discrepancy in the estimates of the effect of p53 expression on DSS between Asians and non-Asians. The same effect of positive/high p53 expression on DSS was observed either in the univariate subgroup (fixed effects: HR 1.47; 95 % CI 1.26–1.71; P = 0.193 for heterogeneity, I2 = 29.5 %) or in the multivariate subgroup (fixed effects: HR 1.64; 95 % CI 1.32–2.03; P = 0.106 for heterogeneity, I2 = 45.0 %). p53 expression and clinicopathological features We also evaluated the association between p53 expression and clinicopathological features of gastric cancer (Table 4). Positive/high p53 expression was statistically significant association with gender (male vs. female: OR 1.26, 95 % CI 1.09–1.45), Lauren’s classification (intestinal type vs. diffuse type: OR 1.68, 95 % CI 1.23–2.29), the depth of invasion (T1/T2 vs. T3/T4: OR 0.68, 95 % CI 0.56–0.83), lymph node metastasis (positive vs. negative: OR 1.56, 95 % CI 1.23–1.97), TNM stage (I/II vs. III/IV: OR 0.57, 95 % CI 0.47–0.69), vascular invasion (positive vs. negative: OR 1.51, 95 % CI 1.18–1.92) and lymphatic invasion (positive vs. negative: OR 1.38, 95 % CI 1.11–1.72), but not with Bormann type (I/II vs. III/IV: OR 1.24, 95 % CI 0.91–1.70), grade of differentiation (1/2 vs. 3/4: OR 1.08, 95 % CI 0.82–1.44) or distant metastasis (positive vs. negative: OR 1.37, 95 % CI 0.92–2.03). Furthermore, no significant heterogeneity between studies was observed in the meta-analysis of the correlation between p53 expression and all clinicopathological features (I2 ranging 0.0–34.7 %) except for Lauren’s classification (I = 67.7 %, P = 0.000) and lymph node metastasis (I2 = 43.9 %, P = 0.021).
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J Cancer Res Clin Oncol
Table 2 Results of the methodological assessment of included studies No. of studies
Designa
Methoda
Generalizabilitya
Results analysisa
Global score (%)
All studies Direct extraction Indirect extraction
34 12 22
P value Asian Non-Asian
5 5.5 5 0.423
6.4 7.2 6.4 0.191
6.7 6.7 6.7 0.736
6.3 6.9 5 0.000
59.7 62.9 58.1 0.017
16 18
4.5 6
6.4 6.4
6.7 6.7
6.3 6.3
59.6 59.7
0.198
0.932
0.646
0.878
P value
0.959
Score distributions are summarized by the median values HR hazard ratio a
Score out of 10
Fig. 2 Forest plot of the overall pooled analysis for the association of p53 expression with OS
Publication bias
Discussion
Both Begg’s funnel plot and Egger’s test were used for assessment of publication bias in the meta-analysis. The shapes of funnel plots did not exhibit obvious asymmetry except for a certain degree asymmetry of studies with the analysis of depth of invasion (Figs. 4, 5). Egger’s test also indicated that there was no significant publication bias (P > 0.05) among studies with overall analysis of OS (P = 0.421), subgroup analysis of OS (P ranging 0.299– 0.691), DSS (P = 0.838) and histopathological features (P ranging 0.115–0.984) except depth of invasion (P = 0.041).
Gastric cancer remains a major health problem due to the slow decline in incidence in Asia and the high mortality in the West, despite advanced diagnostic and operative techniques widely used in clinical practice (Kelley and Duggan 2003; Rivera et al. 2007). The prognosis of gastric cancer varies but is still poor mainly resulting from a high incidence of metastasis and recurrence (Anderson et al. 2006). The TNM staging system for gastric cancer is universally applied in clinical decision-making to provide relevant prognostic information (Huang et al. 2001), but alone, it is
13
J Cancer Res Clin Oncol Table 3 Summarized HRs of overall and subgroup analyses for OS in gastric cancer patients with p53 expression
No. of studies
Overall Ethnicity Asian Non-Asian HR extraction Direct Indirect Sur. analysis Univariate Multivariate Quality score (%) 60
Random effects HR (95 % CI)
Heterogeneity I (%)
P value
21
1.56 (1.23–1.98)
85.7
0.000
10 11
1.64 (1.06–2.54) 1.46 (1.21–1.76)
92.7 38.3
0.000 0.094
7 14
1.98 (1.14–3.45) 1.36 (1.16–1.59)
94.9 29.7
0.000 0.140
15 6
1.41 (1.19–1.68) 1.84 (1.01–3.34)
43.0 95.6
0.039 0.000
2
Meta-regression P value
Egger’s test
0.421 0.682 0.553 0.426 0.139 0.340 0.574 0.326 0.299 0.450 0.249
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1.36 (1.15–1.61)
24.4
0.211
0.691
10
1.80 (1.17–2.76)
92.8
0.000
0.375
Fig. 3 Forest plot of the association of p53 expression with DSS
not adequately accurate. Gastric cancer progression is now considered to be a multistep process implicating growthpromoting and anti-apoptotic signals (Kountouras et al. 2005). Therefore, biological markers may be additionally useful predictors of prognosis for gastric cancer. p53 tumor-suppressor gene and its coded protein play a key role in the signaling of cell cycle arrest and apoptosis. Most mutations in the p53 gene are missense and result in accumulation of p53 in the nucleus. Therefore, p53
over-expression is generally associated with inactivation of p53 (Cordon-Cardo et al. 1994). Based on its functions, positive/high p53 expression in cancer cells may increase proliferative activity of cells, allowing the development and progression of tumor cells and finally leading to a poor prognosis. However, mutations of p53 do not necessarily mean the accumulation of p53 detected by IHC. Gene abnormalities other than missense mutations do not result in accumulations of nuclear protein and therefore escape
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J Cancer Res Clin Oncol
Table 4 Meta-analysis of p53 expression and clinicopathological features of gastric cancer Clinicopathological features
Gender (male vs. female) Bormann type (I/II vs. III/IV) Grade of differentiation (1/2 vs. 3/4) Lauren’s classification (intestinal type vs. diffuse type) Depth of invasion (T1/T2 vs. T3/T4) Lymph node metastasis (P vs. N) Distant metastasis (P vs. N) TNM stage (I/II vs. III/IV) Vascular invasion (P vs. N) Lymphatic invasion (P vs. N)
N
Cases
Analytical model
Pooled OR (95 % CI)
P value
Heterogeneity 2
I (%)
P value
Egger’s test
17 3 6 18
3,830 921 1,078 3,219
FEM FEM FEM REM
1.26 (1.09–1.45) 1.24 (0.91–1.70) 1.08 (0.82–1.44) 1.68 (1.23–2.29)
0.002 0.174 0.572 0.001
0.0 0.0 33.8 67.7
0.943 0.849 0.183 0.000
0.611 0.152 0.115 0.738
17 19 10 12 7
2,566 3,194 1,347 2,221 1,655
FEM REM FEM FEM FEM
0.68 (0.56–0.83) 1.56 (1.23–1.97) 1.37 (0.92–2.03) 0.57 (0.47–0.69) 1.51 (1.18–1.92)
0.000 0.000 0.122 0.000 0.001
7.1 43.9 0.0 34.7 0.0
0.371 0.021 0.456 0.113 0.445
0.041 0.475 0.233 0.957 0.979
5
1,430
FEM
1.38 (1.11–1.72)
0.004
10.6
0.346
0.984
N number of studies, P positive, N negative, REM random-effects model, FEM fixed-effects model, OR odds ratio, CI confidence interval
Fig. 4 Funnel plot of the overall pooled analysis for the association of p53 expression with OS
Fig. 5 Funnel plot of the overall pooled analysis for the association of p53 expression with DSS
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detection by IHC. Some missense mutations lead to a stop codon and may yield a truncated protein that is not detectable by IHC (Fenoglio-Preiser et al. 2003). In addition, there are numerous regulatory mechanisms which modulate p53 activity positively or negatively. For example, some products of the MDM2 oncogene and of viral genes may render p53 unstable and lead to p53 low/negative expression (Li et al. 2004). A physiological response to damaged DNA may lead to over-expression of p53 (Soussi 2000). So far, numerous studies investigated the correlation between p53 expression and the prognosis of gastric cancer but yielded controversial results. To our knowledge, this is the first meta-analysis to quantitatively assess the association between p53 expression and survival as well as clinicopathological features in gastric cancer. In the present meta-analysis, a total of 34 studies comprising 6,599 cases were subjected to final analysis. In the overall pooled analysis of the association of p53 expression with survival in gastric cancer patients, the results suggested that positive/high p53 expression was statistically significantly related to poorer OS (HR 1.56, 95 % CI 1.23–1.98) and DSS (HR 1.52, 95 % CI 1.35–1.73). These findings demonstrated the significance of p53 expression in the prognosis of patients with gastric cancer and were in accordance with theoretical inference that patients with positive/high p53 expression could have a worse clinical prognosis than those with negative/low p53 expression. The same results have been reported in the meta-analyses of other carcinomas, such as hepatocellular carcinoma (Liu et al. 2012a), extrahepatic bile duct carcinoma (Wang et al. 2011), bladder carcinoma (Malats et al. 2005), upper urinary tract urothelial carcinoma (Ku et al. 2013), osteosarcoma (Fu et al. 2013; Pakos et al. 2004), lung carcinoma (Steels et al. 2001) and esophageal carcinoma (Chen et
J Cancer Res Clin Oncol
al. 2013). In the current study, a significant correlation of positive/high p53 expression with OS (P = 0.045) as well as DSS (P = 0.000) was observed in the multivariate subgroup, which suggested that p53 expression may be an independent prognostic indicator of poorer survival, but it should be noted that a significant heterogeneity was presented among the studies with multivariate analysis of OS (I2 = 95.6 %, P = 0.000). In subgroup analysis of OS and DSS according to ethnicity, there was no evidence for ethnical discrepancy in the estimates of the impact of p53 expression on survival between Asians and non-Asians. In addition, nine studies (Bataille et al. 2003; De Dosso et al. 2013; Kubicka et al. 2002; Lim et al. 1996; Migliavacca et al. 2004; Mrozek et al. 2003; Ott et al. 2003; PuhringerOppermann et al. 2006; Solcia et al. 2009) were included to quantitatively assess the association between p53 mutations and survival in patients with gastric cancer (Table S1). p53 mutations were significantly correlated with poorer DSS (fixed effects: HR 1.70, 95 % CI 1.29–2.24; P = 0.189 for heterogeneity, I2 = 42.0 % Fig. S1) but not OS (random effects: HR 1.65, 95 % CI 0.85–3.19; P = 0.001 for heterogeneity, I2 = 72.7 % Fig. S2). However, we found that studies reporting the association between p53 mutations and OS had a small number of cases and significant between-study heterogeneity, which mainly resulted from Bataille et al. (2003). When Bataille et al. (Bataille et al. 2003) was excluded, we reanalyzed the remaining data and observed a significant association between p53 mutations and poorer OS (random effects: HR = 2.08, 95 % CI 1.16– 3.75; P = 0.033 for heterogeneity, I2 = 58.8 %). We also assessed the associations between p53 expression and clinicopathological features; positive/high p53 expression was significantly associated with some of clinicopathological features, such as gender, Lauren’s classification, the depth of invasion, lymph node metastasis, TNM stage, vascular invasion and lymphatic invasion, but not with Bormann type, grade of differentiation and distant metastasis. According to Lauren’s classification (Lauren 1965), gastric cancer is divided into intestinal type and diffuse type. It has been demonstrated that these two histological types have some differences in epidemiology, pathogenesis and clinical outcome (Roder 2002). In this study, we observed that p53 expression was higher in intestinal type compared with diffuse-type gastric cancer, which may be due to the existence of a distinct carcinogenetic pathway between the two histological types of gastric cancer (Zafirellis et al. 2005). Moreover, there were significant relationships between positive/high p53 expression and adverse prognostic features such as a higher incidence of vascular and lymphatic invasion, deeper wall invasion, increased lymph node metastases and a more advanced TNM stage, which may conduce to the understanding of how positive/high p53 expression is correlated with a more
aggressive biological behavior of gastric cancer (Pinto-deSousa et al. 2004) and why positive/high p53 expression is associated with a poorer prognosis in patients with gastric cancer. However, no significant associations between p53 expression and Bormann type, grade of differentiation and distant metastasis were observed in the study; the results may be due to the small sample sizes of studies included in the analysis and need to be further confirmed by the larger sample sizes. In the test of heterogeneity, there was a significant heterogeneity in the analysis of the association of p53 expression with OS in gastric cancer. Although the data were aggregated using the random-effects models, heterogeneity among the studies continued to be a potential problem to influence the reliability of pooled results. Hence, we carried out meta-regression and subgroup analysis according to ethnicity, HR extraction, survival analysis and quality score. However, none of these factors was found to be significantly correlated to heterogeneity using meta-regression analysis, and subgroup analysis still exhibited significant heterogeneity among the studies. The heterogeneity probably results from differences in the baseline characteristics of patients, immunohistochemical methods, the establishment of positive/high p53 expression, the treatments to the patients, the duration of follow-up or others among included studies. Unfortunately, we could not use the available information to further identify the sources of heterogeneity. To verify the stability of the combined results in the meta-analysis, sensitivity analysis was conducted. The combined HRs were not significantly influenced by excluding any individual study and then reanalyzing the remaining data. It should be noted that our meta-analysis has several limitations. Firstly, to reduce the bias from different detection methods, we only included the studies measuring p53 expression by IHC in the meta-analysis. IHC has been widely applied to detect molecular markers of cancer, because the method is simple and fast and agrees with other methodologies (Lee et al. 2003a). However, the differences of the types of antibody, concentration and cutoff value used in IHC might produce potential bias. It is, therefore, necessary to define a standardized protocol and evaluation system to promote the application of molecular markers detected by IHC in clinical practice. Secondly, the variation of methodological quantity among included studies could be a source of bias. The method reported by Steels et al. (Steels et al. 2001) was used as the criteria of quantity assessment in the meta-analysis. Although a significant correlation of p53 expression with OS was observed in two subgroups stratified by quality score, the bias should not be ignored. Thirdly, the approach of HR extraction might result in bias. If HRs with 95 % CIs were not directly reported in the literatures, they had to
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be obtained indirectly from the relevant data or survival curves presented in the articles. In the study, quality scores between the two approaches of HR extraction did exhibit statistically significant deviation. Fourthly, publication bias is a common concern for all meta-analyses (Begg 1988), although no publication bias was found in all relevant analysis except in the analysis of the correlation between p53 expression and depth of invasion. Moreover, the studies included in the meta-analysis were restricted to full publications in English language and could exclude other potentially eligible studies, which also probably resulted in bias. Finally, all of included studies were observational trials, which contained the greater potential confounders and provided the lower level of evidence compared with randomized controlled studies. Therefore, the results should be interpreted cautiously. Despite these limitations, the present study is the first meta-analysis to quantitatively assess the association between p53 expression and survival as well as clinicopathological features in gastric cancer. We concluded that high/positive p53 expression was significantly associated with poorer survival and some adverse clinicopathological features. p53 over-expression may be a useful biomarker to predict a poorer prognosis for gastric cancer patients and to identify a subgroup of patients who may benefit from personalized treatment. However, to strengthen our findings, further larger prospective studies with better standardized methods are needed to make a comprehensive conclusion on the prognostic role of p53 expression in gastric cancer. Acknowledgments This study was supported by the Fundamental Research Funds for the Central Universities (Number: lzujbky-2013-160). Conflict of interest All the authors indicated no potential conflicts of interest.
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