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CRABP2 – A novel biomarker for high-risk endometrial cancer

Published:September 23, 2022DOI:https://doi.org/10.1016/j.ygyno.2022.09.020

      Highlights

      • High CRABP2 expression in endometrial cancer is associated with advanced stage, high grade, and reduced overall survival.
      • Downstream receptors of CRABP2, RARA and RARG, were also implicated in advanced endometrial cancer.
      • A gene signature characterizing differential CRABP2 expression was enriched for Polycomb related gene sets
      • Two master regulators of aberrant CRABP2 expression were identified: BMP7 and ELP3

      Abstract

      Objective

      Investigate the clinical and functional implications of elevated CRABP2 expression in endometrial cancer (EC) patients.

      Methods

      Patients were stratified into high and low CRABP2 expression groups using a decision tree classifier. Univariate and multivariate statistical analyses determined the prognostic and clinicopathological consequences of increased CRABP2 expression. A CRABP2 gene signature was generated using differential expression analysis, and analyzed using network-based approaches. The findings were validated in The Clinical Proteomic Tumor Analysis Consortium (CPTAC), a newly generated cohort of 120 endometrial tissues, and The Cancer Dependency Map (DepMap).

      Results

      60 (11%) patients in TCGA had high CRABP2 expression, whilst 468 (89%) had low expression. High expression was associated with serous EC, reduced overall survival, advanced stage and grade. Downstream retinoic acid receptors (RARG and RARA) were correlated with CRABP2 expression and were associated with worse prognosis in serous EC. The CRABP2 gene signature was enriched for Polycomb target gene sets, and was regulated by ELP3 and BMP7. BMP7 expression was increased in the CRABP2-high group, was associated with worse prognosis, and CRISPR-Cas9 screens revealed correlations in its cell-fitness score with CRABP2 following gene knockout. The opposite was true for ELP3, suggesting opposing effects from both master regulators.

      Conclusions

      CRABP2 expression is associated with poor prognosis and advanced EC. The expression of RARA and RARG correlates with CRABP2 and are associated with worse prognosis in advanced histological subtypes. Polycomb target gene sets and two master regulators, ELP3 and BMP7, were identified as functionally relevant mechanisms driving aberrant CRABP2 expression.

      Keywords

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