The association between MAD2 and prognosis in cancer: a systematic review and meta-analyses

Abstract

This systematic review and meta-analyses investigates the expression of the cell checkpoint regulator, mitotic arrest deficiency protein 2 (MAD2) in cancerous tissue and examines whether an association exists between MAD2 levels and cancer survival and recurrence. Studies investigating MAD2 expression in cancer tissue utilising immunohistochemistry (IHC) were identified by systematic literature searches of Medline, Embase and Web of Science databases by October 2015. Random effects meta-analyses were performed to generate pooled hazard ratios (HRs) with 95% confidence intervals (CIs) of overall and progression-free survival according to MAD2 expression. Forty-three studies were included in the overall review. In 33 studies investigating MAD2 expression by IHC in cancer tissue, a wide range of expression positivity (11-100%) was reported. Higher MAD2 expression was not associated with an increased risk of all-cause mortality in a range of cancers (pooled HR 1.35, 95% CI 0.97-1.87; P = 0.077, n = 15). However, when ovarian cancer studies were removed, a significant pooled HR of 1.59 for risk of all-cause mortality in other cancer patients with higher expressing MAD2 tumours was evident (95% CI, 1.17-2.17; P = 0.003, n = 12). In contrast, higher MAD2 expression was associated with significant decreased risk of all-cause mortality in ovarian cancer patients (pooled HR = 0.50, 95% CI, 0.25-0.97; P = 0.04, n = 3). In conclusion, with the exception of ovarian cancer, increased MAD2 expression is associated with increased risk of all-cause mortality and recurrence in cancer. For ovarian cancer, reduced levels of MAD2 are associated with poorer outcome. Further studies are critical to assess the clinical utility of a MAD2 IHC biomarker.

Keywords: MAD2; cancer; prognosis and systematic review.

Figure 1. Flowchart of study selection that assessed MAD2 immunohistochemistry in cancer

Three databases (Medline, Embase and Web of Science) were utilised to identify potential papers for inclusion in meta-analysis. After removal of duplicates and studies not fulfilling inclusion criteria, data was extracted from these full text papers to be included in meta-analyses evaluating MAD2 percentage expression and both progression-free and overall survival in relation to MAD2 expression.

Figure 2. Meta-analysis of highest v. lowest category of MAD2 protein levels and risk to overall cancer survival

Figure 3. Meta-analysis of highest v. lowest category of MAD2 protein levels and risk to progression free cancer survival