Diagnostic Dilemma: Trans-Spliced RNA Exists in Normal as well as in Cancerous Tissues

Cancer researchers have found that certain gene products, typically used as biomarkers to identify cancer cells, also exist in normal tissues, which may lead to mistakes in diagnosis and untoward side effects from certain anti-cancer drugs.

Chromosomal rearrangements that create gene fusions are common features of human tumors. The prevailing view is that the resultant chimeric transcripts and proteins are abnormal, tumor-specific products that provide tumor cells with a growth and/or survival advantage.

Investigators from Yale University (New London, CT, USA) studied chimeric RNA and proteins in normal and cancerous endometrial tissues. They reported in the September 5, 2008, issue of the journal Science that normal endometrial stromal cells contain a specific chimeric RNA joining 5' exons of the JAZF1 gene on chromosome 7p15 to 3' exons of the Polycomb group gene JJAZ1/SUZ12 on chromosome 17q11, and that this RNA is translated into JAZF1-JJAZ1, a protein with antiapoptotic activity. The chimeric RNA and protein are identical to those produced from a gene fusion found in human endometrial stromal tumors.

"Our findings are surprising because we identified in normal cells certain types of gene products--so called chimeric RNAs and proteins--thought to be found only in cancerous cells or in cells on their way to becoming cancerous,” said senior author Dr. Jeffrey Sklar, professor of pathology and laboratory medicine at Yale University. "Extensive experiments on the normal tissues and cultured cells from those tissues indicated to us that a previously little-known process, the direct splicing together of two RNAs from separate genes--or trans-splicing--is responsible for producing the chimeras.”

These results suggest that the use of chimeric gene products as markers for cancer diagnosis may need to be re-evaluated. Furthermore, cancer drugs that target products of chromosomal abnormalities may display increased toxicity because those same targets may be present in normal cells due to the trans-splicing of RNA.

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