Common Cancers May Involve Fused Genes
New research suggests that gene fusion - the coming together of DNA from different parts of the genome - may be an important event in the development of common cancers.
Fused genes and the chromosomal rearrangements that cause them are a hallmark of leukemia, lymphomas, and other blood cancers, but they were not identified in a solid tumor until 2005. In a landmark study, Dr. Arul Chinnaiyan of the University of Michigan Medical School and his colleagues reported that 70 percent of prostate cancers may harbor fused genes.
Now, a follow-up study on fused genes in prostate cancer by the Michigan group and the first reported study of gene fusion in lung cancer appear in the August 2 Nature. The findings suggest that identifying fusion events could lead to diagnostic tools and targeted therapies modeled on the leukemia drug imatinib (Gleevec), which inhibits the protein product of the fused gene BCR-ABL.
In the lung study, Japanese researchers detected a fused gene in patients with non-small-cell lung cancer (NSCLC). The fusion event between the EML4 and ALK genes activates the ALK tyrosine kinase, which controls other proteins and is likely a factor in the cancer.
Tyrosine kinases are involved in many cancers and have become important drug targets. For instance, the kinase inhibitors erlotinib (Tarceva) and gefitinib (Iressa) have benefited lung cancer patients with mutations in the EGFR or HER2/neu genes.
The structure of the EML4-ALK fusion gene suggests that it might be a potential drug target, researchers from the Jichi Medical University report in Nature. They found the EML4-ALK fusion in 5 of 75 patients studied.
Given the need for potential drug targets in common cancers, the discovery is "momentous," says Dr. Matthew Myerson of the Dana-Farber Cancer Institute in a commentary.
In the prostate study, Dr. Chinnaiyan and his team identified additional gene fusions in prostate tumors. These gene fusions represent distinct types of chromosome rearrangements, and each type may be associated with distinct subtypes of prostate cancer.
Each subtype may require a therapy tailored to the underlying genetic flaw, as is the case for the subtypes of leukemia, the researchers say.
Some fusion events create hybrid genes that are activated by androgen hormones, which can fuel prostate cancer growth. But others do not. For example, one of the identified fusion genes is inactivated by androgens. Androgens have no effect on the activity of yet another identified fusion gene.
This information may prove useful to physicians in making decisions about whether to use hormone therapy in individual patients.
Dr. Chinnaiyan's team also reports that the fusion genes were sufficient to cause prostate cancer in cells and animal models of prostate cancer.
"This is the first study to show that the products of gene fusions initiate an oncogenic cascade in cells or animal models," says Dr. Chinnaiyan. He is supported by NCI's Early Detection Research Network and the Specialized Program of Research Excellence in prostate cancer.
Together, the findings on lung and prostate cancers suggest that activated fusion genes that result from chromosomal rearrangements "are probably both common and important in solid tumors," notes Dr. Myerson.
Discovering the fusions and using them in clinical practice could provide "a great leap forward" in understanding the causes of common cancers, he adds.
— Edward R. Winstead