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Evidence that public database records for many cancer-associated genes reflect a splice form found in tumors and lack

Meenakshi Roy1, Qiang Xu, Christopher Lee

  • 1Molecular Biology Institute, Center for Genomics and Proteomics, Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, CA 90095-1570, USA.

Nucleic Acids Research
|September 9, 2005
PubMed

Insights

Many cancer-associated genes have previously unknown splice forms in normal tissues. Re-evaluating these normal splice forms is crucial for understanding gene function in both health and cancer.

Area of Science:

  • Genomics
  • Molecular Biology
  • Bioinformatics

Background:

  • Alternative splicing generates diverse transcript isoforms from a single gene.
  • Cancer tissues often exhibit distinct splice forms compared to normal tissues.
  • Existing cDNA databases may not fully represent normal tissue transcriptomes due to historical cloning biases from tumor samples.

Purpose of the Study:

  • To identify novel splice forms, particularly in-frame exon skipping events, in normal human tissues for a panel of 50 cancer-associated genes.
  • To assess the representation of normal versus tumor-associated splice forms in public databases.
  • To provide a comprehensive database of novel normal splice forms.

Main Methods:

  • Bioinformatic analysis of gene sequences.
  • Reverse transcription polymerase chain reaction (RT-PCR) on normal tissue samples.
  • Comparison of identified splice forms with existing databases like GenBank.

Main Results:

  • Previously unknown splice forms were identified in normal tissues for nearly two-thirds of the studied cancer-associated genes.
  • Approximately 40% of these novel normal splice forms were found to be the dominant splice form.
  • Tumor-associated splice forms were twice as prevalent in GenBank compared to normal tissue forms, reflecting cloning biases.
  • A novel normal splice form of IKBbeta, a key regulator of the NF-kappaB pathway, was identified.
  • A database of 1308 novel normal splice forms was compiled.

Conclusions:

  • Normal tissues harbor a significant number of previously undiscovered splice forms for cancer-associated genes.
  • The current understanding of transcript isoforms in public databases is skewed towards tumor-associated forms.
  • Systematic investigation of normal tissue splice forms is essential for a complete understanding of gene function in normal physiology and cancer pathogenesis.

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