Search results and study characteristis
976 articles were identified by searching the PubMed, Embase, Web of science and Cochrane library. We excluded 941 articles after screening the titles and abstracts. Then we included 12 studies after reviewing 43 Full-text articles in detail[9-20]. A flowchart of the retrieval process is shown in Fig.1. Among the included studies, all of them reported the correlation of YAP expression with OS, 10 records evaluated the relationship between YAP and clinicopathological signification in patiens with CRC. 7 studies provided Hazard ratio(HR) statistic in the original literature, and others were determined from the Kaplan-Meier curve by using Engauge Digitizer 10.0 sofeware. There were 2286 patients with sample size ranging between 66 and 903. Most of studies were from china except one from Korea. A summary of the main characteristics of the included studies is shown in Table 1. Immunohistochemical techniques and qRT-PCR were used to defined for YAP expression levels. All patients were divided into two groups: high and low YAP expression group. The relationship between high expression of YAP and clinicopathological features in CRC patients is shown in the table 2 , whereas the low expression of YAP is shown in the table3.
Association of YAP and OS
In the meta-analysis of OS, 12 studies with a total of 973 patients were included. The forest results are shown in fig.2. The pooled hazard ratio (HR) evaluated for OS was (2.02,95%CI 1.67-2.44 P=0.05) in CRC patients(Fig.2a). A fixed-effects was used for no no heterogeneity (I2=19.7% P= 0.25). The pooled results suggested that high YAP expression could be a reliable biomarker to predicate the endpoint in CRC patients.
Next we proceeded with subgroup analyses stratified by HR obtained measurements, NOS score and sample capacity. When it came to the HR obtained measurements, pooled HR was (1.69 95%CI 1.18-2.44) for the records with indirect method subgroup with no heterogeneity (I2=0.0%,P=0.857) and direct method subgroup (HR:2.05 ,95%CI 1.72-2.44 , I2=47.9% P=0.073) (Fig2b). The combined HR for high and low NOS score were HR 2.20 (95%CI 1.65-2.93 I2=0.0% P=0.453) and HR 1.89 (95%CI 1.57-2.29 I2=38.0% P=0.153) (Fig.2c). In addition , the high expression YAP predicted a worse OS in studies with sample capacity > 100 HR (2.06 95%CI 1.74-2.44, I2=39.6% P=0.115) while there was no significant difference between YAS overexpression and OS in records with size < 100 (HR=1.48 95%CI 0.95-2.31 , I2 0.0%, P=0.968) (Fig.2d)
Association of YAP expression with tumor clinicopathological features
In this meta-analysis, 6 studies were identified the relationship between TNM and YAP in CRC, 4 studies about tumor invasion depth, 6 records about lymph node metastasis and 5 records about distant metastasis . The main results are listed in the Fig3. High expression of YAP was associated with advanced TNM stage (OR 2.99 , 95%CI 2.11-4.25, I2=0.0%, P=0.699), Lymph node metastasis (OR 3.73, 95%CI 2.63-5.30, I2=4.8%, P=0.386), distant metastasis (OR 3.03, 95%CI 1.21-7.56, I2=65.3%, P=0.021) but had no association with tumor invasion depth (OR:1.91 ,95%CI 0.75-4.83 , I2=70.3%, P=0.018). The results show heterogeneity across the included studies about tumor invasion depth. However, after removing the study by Fang et al, the OR(2.82 95%CI 1.65-4.83 I2=0.0%, p=0.413) has a significant. We though YAP expression still had a significant impact on tumor invasion depth. Our results demostrated that CRC patients with high expression of YAP tended to have distant metastasis , lymph node metastasis , advanced TNM stage and deep tumor invasion depth and having a worse outcome in clinic features.
With respect to the other parameters (sex, tumor size, tumor differentiation, tumor location), we could not find a significant association as shown in Fig.4. High expression of YAP was associated with sex (male vs female) (OR 0.89 ,95%CI 0.68-1.17 , I2= 17.4%, p= 0.288), tumor size(≥3cm vs <3cm) (OR 1.27 ,95%CI 0.87-1.83 , I2= 28.8%, p= 0.219), Tumor differentiation(poorly vs moderately and well) (OR 1.21 ,95%CI 0.45-3.82 , I2= 78.3%, p= 0.001), Tumor location(colon vs rectum) (OR 0.85 ,95%CI 0.54-1.33 , I2= 2%, p= 0.395).
Publication bias
In this meta-analysis, we used Begg’s funnel plots and Egger’s test to assess the publication bias between YAP expression levels and OS in colorectal carcinoma patients. Begg’s test indicated no obvious evidence for publication bias(Fig.5). In addition, a similar result was abtained in Egger’s test (p=0921). However, we did’t check the publication bias between YAP and clilicopathological features due to the limited number of included records.
Sensitivity analysis
Sensitivity analysis was used to assess the reliability and stability of our results by removing any separate study(Fig.6). This indicated that the result of this meta-analysis were reliable.