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A kernel density estimation-based approach for quantifying O-GlcNAcylation dysregulation in cancer from gene

Rastko Stojšin1, Jinlian Wang1, Hongfang Liu1

  • 1Center for Translational AI Excellence and Applications in Medicine, D. Bradley McWilliams School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX 77030, United States.

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Summary

O-GlcNAcylation dysregulation in cancer can now be quantified using O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) expression. This new transcriptomics-based method accurately infers and classifies cancer status, offering a scalable approach for large-scale studies.

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Area of Science:

  • Biochemistry and Molecular Biology
  • Cancer Research
  • Bioinformatics

Background:

  • O-GlcNAcylation is a crucial post-translational modification impacting biological processes and cancer development.
  • Measuring O-GlcNAcylation directly is difficult due to its instability and low-throughput methods.
  • OGT and OGA expression levels offer a simpler way to infer O-GlcNAcylation dysregulation.

Purpose of the Study:

  • To develop a novel, scalable method for quantifying O-GlcNAcylation dysregulation using gene expression data.
  • To validate the method's accuracy in simulated and real-world cancer datasets.
  • To enable large-scale analysis of O-GlcNAcylation patterns in cancer.

Main Methods:

  • Developed a nonparametric kernel density estimation approach using joint OGT and OGA expression.
  • Utilized simulated datasets with controlled dysregulation levels for method validation.
  • Applied the method to The Cancer Genome Atlas (TCGA) data from six cancer types.

Main Results:

  • The proposed method accurately quantified O-GlcNAcylation dysregulation, outperforming existing metrics.
  • Inferred regulation scores were significantly lower in cancer samples compared to healthy controls.
  • The method achieved accurate cancer status classification (AUROC: 0.71-0.75) and generalized to external datasets.

Conclusions:

  • A transcriptomics-based framework provides a scalable and interpretable method for quantifying O-GlcNAcylation dysregulation in cancer.
  • This approach overcomes limitations of direct measurement, facilitating large-scale cancer research.
  • The freely available code and data promote further investigation and application of this method.