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Meta-analysis of the diagnostic value of Wisteria floribunda agglutinin-sialylated mucin1 and the prognostic role of mucin1 in human cholangiocarcinoma

Objective Serum carbohydrate antigen 19–9 (CA19-9) is a widely used tumour marker for cholangiocarcinoma (CCA). However, it is not a necessarily good CCA marker in terms of diagnostic accuracy. The purpose of this study is to evaluate the diagnostic value of Wisteria floribundaagglutinin-sialylated Mucin1 (WFA-MUC1) and the prognostic role of Mucin1 (MUC1) in human CCA. Design Meta-analysis. Data sources Studies published in PubMed, Web of Science, The Cochrane Library and the China National Knowledge Infrastructure up to 11 October 2017. Eligibility criteria We included reports assessing the diagnostic capacity of WFA-MUC1 and the prognostic role of MUC1 in CCA. The receiver operating characteristic curve (ROC) of WFA-MUC1 and/or CA19-9 was described, and the HRs including 95% CI and the corresponding p value for MUC1 can be extracted. Data extraction and synthesis Two independent researchers extracted data and assessed risk of bias. The diagnostic sensitivity and specificity data of WFA-MUC1 were extracted and analysed as bivariate data. Pooled HRs and its 95% CI for MUC1 were calculated with a random-effects meta-analysis model on overall survival of resectable CCA. Results Sixteen reports were included in this study. The pooled sensitivity and specificity of WFA-MUC1 were 0.76 (95% CI 0.71 to 0.81) and 0.72 (95% CI 0.59 to 0.83) in serum, 0.85 (95% CI 0.81 to 0.89) and 0.72 (95% CI 0.64 to 0.80) in bile and 0.72 (95% CI 0.50 to 0.87) and 0.85 (95% CI 0.70 to 0.93) in tissue, respectively. The summary ROC (SROC) were 0.77 (95% CI 0.73 to 0.81) in serum, 0.88 (95% CI 0.85 to 0.90) in bile and 0.86 (95% CI 0.83 to 0.89) in tissue, respectively. Furthermore, the pooled sensitivity and specificity and the SROC of CA19-9 in serum were 0.67 (95% CI 0.61 to 0.72), 0.86 (95% CI 0.75 to 0.93) and 0.75 (95% CI 0.71 to 0.79), respectively. The pooled HRs for MUC1 was 2.20 (95% CI 1.57 to 3.01) in CCA and 4.17 (95% CI 1.71 to 10.17) in mass-forming intrahepatic CCA. Conclusions Compared with CA19-9, WFA-MUC1 was shown to possess stronger diagnostic capability. MUC1 could serve as a prognosis factor for poor outcomes of CCA, particularly, mass-forming intrahepatic CCA.


GENERAL COMMENTS
The review is interesting and is timely. Mucin histochemistry is a tedious business and many reports are available to show that in practice. This difficulty arises from the fact that both protein core and glycosylation influence reactivity of the mucin. Even more, some antibodies recognize glycosylation specific glycotopes. This should be discussed in more detail. See e. g.: Schumacher U, Adam E. Immunohistochemical detection of the MUC1 gene product in human cancers grown in scid mice. J Histochem Cytochem. 1998 Jan;46 (1) The writing of this manuscript should be improved. The current version contains many typos and grammar mistakes. For example, "matthew" should be "Matthew" at the bottom of page 7, the web link in the second line on page on page 8 did not display properly, the subtitle "... and publication Bias" should be "... and publication bias". On page 10, "Nine studies evaluating ..." should be "Nine studies evaluated ...", and there were many similar issues like this.
The materials about assessing publication bias in the middle of page 8 were repeated in the middle of page 9. This is unnecessary. Also, cite Egger's paper (Egger et al., 1997, BMJ) when Egger's regression test is mentioned. Usually, for publication bias tests, P < 0.1 (not 0.05) is considered significant because their statistical power is often low.
In Figure 1 On page 12, "Egger's test P > 0.134". Why not present the exact P value?

Reviewer 1#
Comment 1: As there are many candidate markers for CCA reported, the authors should provide the rational why MUC1 was selected as the marker for CCA in this study.
Response: : Thank you very much for asking this question. As previous published literatures, many candidate markers for CCA such as IL6 (interleukin6), serum cytokeratin19 fragments, mucin2~6, serotonin, tumor type M2 pyruvate kinase, etc. involved in this system, However, the clinical applicability of most existing markers is limited due to a lack of adequate sensitivity and specificity compared with CA19-9, the most used serum tumour marker for CA19-9. Furthermore, the vast majority of existing markers for CAA reported by handful research with a limited number of participants.
Recently  (2):218-228) in their publications included a large number of participants reported that Wisteria floribunda agglutinin-sialylated mucin 1 (WFA-MUC1) had a high diagnostic capability compared with CA19-9 in discriminating CCA from benign biliary disease, which is an encouraging thing for us. However, the various diagnostic capability has been reported by previous studies, the optimal diagnostic capability of WFA-MUC1 remains unclear as we described in the "Introduction Section" of our manuscript. As described above, that's the reason why we focused on MUC1 in this study. Response: Thanks for the suggestions. As suggested, we searched the GO classification system (http://www.pantherdb.org/) to found the Molecular Function (MF), Biological Process (BP) and Reactome Pathways of MUC1 in cancer, which was summarized in Table 4.. Response: Sorry for the typo. We had corrected the typing errors caused by our carelessness in writing and provided the full words of each abbreviation at the first presentation.

Reviewer 2#
Comments: The review is interesting and is timely. Mucin histochemistry is a tedious business and many reports are available to show that in practice. This difficulty arises from the fact that both protein core and glycosylation influence reactivity of the mucin. Even more, some antibodies recognize glycosylation specific glycotopes. This should be discussed in more detail. See e. g.: Schumacher U, Adam E. Immunohistochemical detection of the MUC1 gene product in human cancers grown in scid mice. J Histochem Cytochem. 1998 Jan;46(1):127-34. PubMed PMID: 9405502.

GO BP Complete
transcription by competitive promoter binding, regulation of transcription from RNA polymerase II promoter in response to stress, cytokine-mediated signaling pathway, negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator, O-glycan processing, positive regulation of histone H4 acetylation, stimulatory C-type lectin receptor signaling pathway  (2):259-263). Thereafter, Matsuda et al. and following researchers investigated the diagnostic capability of Wisteria floribunda agglutinin sialylated-mucin1(WFA-MUC1) in serum or bile sample collected from cholangiocarcinoma patients. As Table 2 showed, all included reports used WFA-MY.1E12 to detect the concentration of MUC1 in serum or bile, so the methodology of detecting the MUC1 in bile or serum was consistent as described in the "Method and Material" section of included studies.

Reactome Pathways
It's a truth that the antibody is detecting the MUC1 in cancer tissue was not identical among the included studies, as Table 3 depicted. However, these antibodies were designed to identify the epitope of MUC1, not the glycan associated with MUC1. Due to the various criteria of positive or high expression of MUC1 in tissue, a further analysis cloud not be performed to determine which is better about the methodologies.