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Using Human Differentially Expressed Gene Lists to Perform Downstream Pathway Enrichment Analysis and Target Prioritization
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Why do pathway methods work better than they should?

Bence Szalai1, Julio Saez-Rodriguez2,3

  • 1Department of Physiology, Faculty of Medicine, Semmelweis University, Budapest, Hungary.

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|December 3, 2020
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Summary
This summary is machine-generated.

Cancer pathway analysis may not reflect pathway activity but rather changes in transcription factor (TF) activities. This is because gene sets in pathways often overlap with genes regulated by TFs, not necessarily correlated with protein activity.

Keywords:
gene expressiongene setpathway activitytranscription factor

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Area of Science:

  • Bioinformatics
  • Molecular Biology
  • Cancer Research

Background:

  • Pathway analysis is common in cancer research using gene expression data.
  • Current methods infer pathway activity from gene expression, but protein activity ultimately drives pathways.
  • The link between gene expression and protein activity is not fully understood.

Purpose of the Study:

  • To investigate the underlying mechanism of pathway analysis effectiveness in cancer gene expression data.
  • To challenge the assumption that gene expression directly reflects pathway activity.
  • To propose an alternative explanation for the success of pathway-based methods.

Main Methods:

  • Analysis of cancer gene expression datasets.
  • Comparison of pathway gene sets with transcription factor (TF) target gene sets.
  • Evaluation of the correlation between gene expression and inferred pathway activity versus TF activity.

Main Results:

  • Pathway analysis success is linked to overlaps between pathway gene sets and TF-regulated genes.
  • Gene expression changes in pathways do not necessarily correlate with protein activity.
  • Inferred pathway activity often reflects underlying TF activity changes.

Conclusions:

  • Pathway analysis methods may indirectly measure TF activity rather than direct pathway activity.
  • The effectiveness of pathway analysis in cancer research might be due to TF regulation, not pathway gene expression correlation.
  • Re-evaluation of pathway analysis interpretation in cancer genomics is warranted.