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Year : 2018  |  Volume : 14  |  Issue : 9  |  Page : 433-436

Serum B7 homologous body 4 for the diagnosis of ovarian cancer in Chinese Han women: A meta-analysis

1 Department of Obstetrics and Gynecology, West China Second Hospital, Sichuan University, Chengdu, Sichuan 610041, China
2 Department of Medical Informatics, West China School of Medicine, Sichuan University, Chengdu, Sichuan 610041, China

Date of Web Publication29-Jun-2018

Correspondence Address:
Mingrong Xi
Department of Obstetrics and Gynecology, West China Second Hospital, Sichuan University, No. 20, 3rd Section, South Renmin Road, Chengdu, Sichuan 610041
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1482.177216

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 > Abstract 

Objective: The aim of this study is to investigate the clinical value of serum B7 homologous body 4 (B7-H4) protein detection for the diagnosis of ovarian cancer (OC) in Chinese Han women by pooling published data.
Methods: A systematic literature search was conducted in Cochrane Library, PubMed, EMBASE, Wanfang, and China National Knowledge Infrastructure databases. The bivariate model was utilized to calculate the pooled estimates. Publication bias was assessed by using funnel plots and Deek's test.
Results: After the review, ten publications were found to meet our inclusion criteria. The overall diagnostic sensitivity and specificity of B7-H4 in OC were 0.782 (95% confidence interval [CI]: 0.732–0.825) and 0.870 (95% CI: 0.804–0.916), respectively. The area under summary receiver operating characteristic curves was 0.86 (95% CI: 0.83–0.89). No significant publication bias was observed in the included studies.
Conclusion: Serum B7-H4 detection, either alone or in combination with carbohydrate antigen 125, has an acceptable value in the diagnosis of OC.

Keywords: B7 homologous body 4, carbohydrate antigen 125, diagnosis, meta-analysis, ovarian cancer

How to cite this article:
Lan Z, Fu D, Xi M. Serum B7 homologous body 4 for the diagnosis of ovarian cancer in Chinese Han women: A meta-analysis. J Can Res Ther 2018;14, Suppl S2:433-6

How to cite this URL:
Lan Z, Fu D, Xi M. Serum B7 homologous body 4 for the diagnosis of ovarian cancer in Chinese Han women: A meta-analysis. J Can Res Ther [serial online] 2018 [cited 2019 Nov 11];14:433-6. Available from: http://www.cancerjournal.net/text.asp?2018/14/9/433/177216

 > Introduction Top

Ovarian cancer (OC) is the third most common tumor in the female genital tract [1] and is the major cause of all cancer-related deaths for women in most developed countries. The high mortality rate of OC is mainly attributable to the lack of obvious symptoms and noninvasive screening methods in its early stages.[2] To improve the prognosis for OC patients, developing useful early diagnostic biomarkers to achieve early treatment is desirable.

In 2006, Simon et al.[3] demonstrated that B7 homologous body 4 (B7-H4), a type-I transmembrane protein, can be measured in the tissue lysates, sera, and ascites of women with OC. In addition, they reported that preoperative serum B7-H4 levels are significantly higher in ovarian neoplasm patients than in healthy blood donors.[4] The diagnostic accuracy of B7-H4 detection for OC has been extensively studied in Chinese Han women; therefore, our meta-analysis aims to ascertain whether B7-H4 is a promising tumor biomarker in future screening tests for ovarian carcinoma.

 > Methods Top

Search strategy

Cochrane Library, MEDLINE (PubMed database), Wanfang, and China National Knowledge Infrastructure databases were searched for all related articles up to July 2015. Search keywords included “B7 homologous body 4/B7-H4” and “ovarian neoplasms” or “ovary cancers.” In addition, the references of relevant review articles were manually searched.

Selection criteria

A study was included in this meta-analysis if it met the following criteria: (1) it provides B7-H4 values for both sensitivity and specificity of the diagnosis of OC. (2) It includes, at least, ten specimens to avoid selection bias. (3) The full text is written in English or Chinese. (4) The patients are Chinese Han women. (5) The OC patients are confirmed by histopathologic examinations (gold standard).

If overlapping patient cohorts were used among multiple studies, only the latest or the largest study was retained after careful reexamination. Two reviewers independently evaluated study eligibility, and disagreements were resolved in a consensus meeting.

Data extraction and quality assessment

The data retrieved from the reports included author name, publication year, study characteristics, sample size, type of control group, sensitivity and specificity data, and cut-off level. The quality assessment for studies of the diagnostic accuracy (maximum score of 14) tool [5] was employed to assess the methodological quality of eligible studies. Any discrepancy between the two reviewers was resolved through a discussion and consultation with a third reviewer.

Statistical analyses

The pooled sensitivity, specificity, positive and negative likelihood ratios (PLR and NLR), diagnostic odds ratio (DOR), and their 95% confidence intervals (CIs) in the diagnosis of B7-H4 were calculated with the bivariate model. We utilized the Chi-square test and the I-squared value (I2) to detect statistically significant heterogeneity across studies. Subgroup analysis was performed to explore the possible sources of heterogeneity in the eligible studies. Funnel plots and Deek's test were used to examine publication bias.[6] All tests were two-sided, and a P < 0.05 was regarded as statistically significant. Stata 13.0 software (Stata Corporation; College Station, Texas, USA) was employed for statistical analysis.

 > Results Top

Study selection and characteristics analysis

Through an initial electronic search, a total of 142 records related to the searched keywords were obtained. After an independent review, ten publications that assessed the relationship of B7-H4 serum levels and OC in Han populations were considered eligible for inclusion in this meta-analysis. We noted that four studies also evaluated the role of B7-H4 combined with carbohydrate antigen 125 (CA-125) in the diagnosis of OC in the enrolled studies [Table 1].[7],[8],[9],[10],[11],[12],[13],[14],[15],[16] The characteristics and quality scores of the selected studies are presented in [Table 2].
Table 1: Diagnostic value of B7 homologous body 4 and B7 homologous body 4 in combination with carbohydrate antigen 125 in individual studies

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Table 2: Characteristics of studies included in the analysis

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Diagnostic accuracy

The I2 values of sensitivity and specificity were 44.00% (95% CI: 2.85–85.15) and 68.99% (95% CI: 48.64–89.35), respectively, indicating a significant heterogeneity among the enrolled studies.

The overall diagnostic sensitivity and specificity of B7-H4 in OC patients based on the bivariate model were 0.782 (95% CI: 0.732–0.825) and 0.870 (95% CI: 0.804–0.916), respectively [Figure 1]. The pooled PLR was 6.026 (95% CI: 3.985–9.110), NLR was 0.251 (95% CI: 0.204–0.307), and DOR was 24.043 (95% CI: 14.730–39.245).
Figure 1: The forest plot of analyses for diagnostic sensitivity and specificity. Abbreviations: CI: Confidence interval; df: Degrees of freedom

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According to the graphs of summary receiver operating characteristic curve (SROC), the area under the curve (AUC) for B7-H4 in OC diagnosis was 0.86 (95% CI: 0.83–0.89) [Figure 2]. The diagnostic performances of single B7-H4 and B7-H4 combined with CA-125 were compared in [Table 3].
Figure 2: The summary receiver operating characteristic curves of the meta-analysis. Abbreviations: SROC: Summary receiver operating characteristic; AUC: Area under curve

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Table 3: The pooled diagnostic performance of single B7 homologous body 4 versus B7 homologous body 4+ carbohydrate antigen 125

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Subgroup analysis and publication bias

As shown in [Table 4], compared with the nonhealthy control group, the healthy control group performed better in the tests: AUC (95% CI) B7-H4: healthy control 0.88 (0.85–0.90) > nonhealthy control group 0.85 (0.82–0.88).
Table 4: Subgroup analysis

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The funnel plots for publication bias [Figure 3] showed symmetry for serum B7-H4 studies, and Deek's test was not significant (B7-H4: P = 0.329). These results indicate that publication bias is not significant.
Figure 3: The funnel plot of publication biases

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 > Discussion Top

Noninvasive detection of OC has been attempted with ultrasonography and serum biomarkers such as CA-125.[17] The latter promises to provide an acceptable positive predictive value and to be cost effective.[18] Although CA-125 is typically used for disease detection and monitoring of therapy in OC patients, a number of benign gynecologic diseases [19] and nongynecologic malignancies are associated with elevated CA-125 serum levels. Currently, considerable efforts are underway to identify new biomarkers in OC detection.

B7-H4, a modulator of negative regulation in T-cell-mediated immunity,[20] is one of the most studied biomarkers for OC. This protein plays a significant role in the “immune escape” theory of tumors, and its overexpression has been identified in cancers of the breast, stomach, and kidney. Tringler et al.[21] reported that consistent overexpression of B7-H4 occurs in serous, endometrioid, and clear cell ovarian carcinomas but is absent in normal ovaries.

Simon et al.[3] showed that the sensitivity of OC detection increases from 52% for CA-125 alone to 65% with 97% specificity when used in combination with B7-H4. The same authors further demonstrated that serum B7-H4 levels do not change during pregnancy and, unlike CA-125, B7-H4 does not increase in patients with inflammatory diseases (asthma, bronchitis, or Crohn's disease). In this meta-analysis, the SROC analysis revealed that the combined detection of B7-H4 and CA-125 for OC had a higher AUC than B7-H4 alone (0.94 vs. 0.86). These data indicate that B7-H4 might be a promising adjunct to CA-125 for the detection of ovarian carcinoma.[22]

Nevertheless, this meta-analysis has several limitations. First, four studies recruited healthy individuals as the control group; under such circumstances, the diagnostic values of B7-H4 may be overestimated [Table 4]. Second, although all OC patients involved in the studies were confirmed by a histopathological examination, not all the control groups received confirmation by the same “gold standard.” Therefore, partial verification bias could not be avoided.[23] Third, the exclusion of conference abstracts and unpublished data may have resulted in potential publication bias. Despite these limitations, this is the first meta-analysis of the diagnostic accuracy of B7-H4 for OC, suggesting that B7-H4 is a useful tumor biomarker in future screening tests.

 > Conclusion Top

This meta-analysis provides evidence that serum B7-H4 detection, either alone or in combination with CA125, has an acceptable value in the diagnosis of OC. Additional studies with multicenter trials and carefully selected controls should be performed to further determine the clinical use of B7-H4 as an effective tumor marker of OC.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

 > References Top

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Dou YH, Wu XJ, Jiang Y. Research on the content changes of the serum markers B7-H4 molecules and its role in the diagnosis of ovarian cancer. Chin J Pharm Anal 2010;30:570-2.  Back to cited text no. 12
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Xu CJ. The applicative value of TV3D-CPA technology combined with determination on serum B7-H4, CA125 in ovarian neoplasms. Zhejiang Clin Med J 2014;16:1248-9.  Back to cited text no. 15
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Rosen DG, Wang L, Atkinson JN, Yu Y, Lu KH, Diamandis EP, et al. Potential markers that complement expression of CA125 in epithelial ovarian cancer. Gynecol Oncol 2005;99:267-77.  Back to cited text no. 18
Niloff JM, Klug TL, Schaetzl E, Zurawski VR Jr., Knapp RC, Bast RC Jr. Elevation of serum CA125 in carcinomas of the fallopian tube, endometrium, and endocervix. Am J Obstet Gynecol 1984;148:1057-8.  Back to cited text no. 19
Sica GL, Choi IH, Zhu G, Tamada K, Wang SD, Tamura H, et al. B7-H4, a molecule of the B7 family, negatively regulates T cell immunity. Immunity 2003;18:849-61.  Back to cited text no. 20
Tringler B, Liu W, Corral L, Torkko KC, Enomoto T, Davidson S, et al. B7-H4 overexpression in ovarian tumors. Gynecol Oncol 2006;100:44-52.  Back to cited text no. 21
Simon I, Liu Y, Krall KL, Urban N, Wolfert RL, Kim NW, et al. Evaluation of the novel serum markers B7-H4, Spondin 2, and DcR3 for diagnosis and early detection of ovarian cancer. Gynecol Oncol 2007;106:112-8.  Back to cited text no. 22
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  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2], [Table 3], [Table 4]


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