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Failure to Detect Mutations in U2AF1 due to Changes in the GRCh38 Reference Sequence.

Christopher A Miller1, Jason R Walker2, Travis L Jensen3

  • 1Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri; Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri.

The Journal of Molecular Diagnostics : JMD
|January 18, 2022
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Summary
This summary is machine-generated.

A change in the GRCh38 human reference build hinders the detection of crucial U2AF1 gene mutations in cancers like leukemia. This study presents a modified GRCh38 reference to improve mutation identification.

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Area of Science:

  • Genomics
  • Cancer Biology
  • Bioinformatics

Background:

  • The U2AF1 gene is vital for mRNA splicing and its mutations are implicated in oncogenesis.
  • Somatic mutations in U2AF1 are frequently observed in myelodysplastic syndrome, acute myeloid leukemia, and other cancers.
  • Current variant calling pipelines fail to detect U2AF1 mutations due to a specific alteration in the GRCh38 human reference build.

Purpose of the Study:

  • To detail the technical problem caused by the GRCh38 reference build affecting U2AF1 mutation detection.
  • To propose and validate a solution for accurately identifying U2AF1 mutations in cancer genomics.

Main Methods:

  • Comparative analysis of variant calling results using standard vs. modified GRCh38 reference builds.
  • Detailed examination of the specific genomic alteration in GRCh38 impacting U2AF1.
  • Development and testing of a modified GRCh38 reference with preserved coordinates.

Main Results:

  • The GRCh38 reference build contains a change that masks U2AF1 gene mutations.
  • A modified GRCh38 reference build, maintaining original coordinates, successfully enables detection of these mutations.
  • The proposed modification resolves issues in variant calling pipelines for U2AF1 and potentially other affected genes.

Conclusions:

  • The GRCh38 reference build poses a significant challenge for U2AF1 mutation detection in cancer research.
  • A modified GRCh38 reference build offers a practical solution to improve diagnostic accuracy and facilitate cancer research.
  • This work highlights the importance of reference genome integrity for accurate variant analysis in clinical and research settings.