How Gene Fusions May Occur in Prostate Cancer
Four years ago, researchers at the University of Michigan Medical School uncovered a common genetic change in prostate cancer—fused genes. These mutant genes, which have since been found in other common cancers, form when DNA from different parts of the genome merge. The mechanisms underlying these changes are poorly understood.
Now, the Michigan team, led by Dr. Arul Chinnaiyan and supported in part by NCI’s Early Detection Research Network, has recreated gene fusions in the laboratory. They show that exposure to male hormones called androgens can cause chromosomes to change their three-dimensional positions in a cell, bringing into proximity genes that are normally far apart. When this occurs in a cell that experiences DNA damage, genes from different chromosome regions may fuse together.
Gene fusions may therefore be the product of a two-step process, the researchers reported online October 30 in Science. The study was done using prostate cancer cells that lacked gene fusions but were sensitive to androgens, which play a role in some prostate cancers. The cells were exposed to dihydrotestosterone, a modified version of testosterone, and then to radiation. Higher doses of radiation were associated with more fusion events.
“Gene fusions in prostate cancer are caused by a combination of androgen signaling and DNA-damaging agents,” said Dr. Chinnaiyan. While the researchers had thought that these events could occur by chance, this study suggests that androgens may set the stage for at least some types of fusions.
A study last year reported that the hormone estrogen could induce positional changes in chromosomes and bring together genes that were normally far apart. Because of the similarities between androgen and estrogen signaling in cells, the researchers hypothesized that androgens may induce chromosomal movements in prostate cancer.
“We have known that androgens can regulate genes, and it now appears that the hormones can induce intra-chromosomal movements,” said Dr. Ram-Shankar Mani, the study’s first author. Future studies are needed to unravel the molecular mechanisms underlying the chromosomal changes and fusion events.
The researchers focused on the fusion of two genes on chromosome 21 that normally reside far apart, TMPRSS2 and ERG. This fusion occurs in approximately half of prostate cancers and may drive the disease.
The Michigan group plans to investigate other fusions, as well. “We focused on the most common gene fusion associated with prostate cancer, but we believe that many genes will come into proximity because of androgen signaling,” said Dr. Chinnaiyan.
These findings have important implications for understanding the cell type-specific three-dimensional architecture of the nucleus, commented Dr. Steven Smith, Professor of Molecular Science at City of Hope in Duarte, CA, who was not involved in the research.
“This study really highlights the cross-fertilization between cancer biomarker research and basic biology,” Dr. Smith wrote in an e-mail message. “One usually thinks that basic science drives cancer research but often, as in this study, it can be the other way around.”
—Edward R. Winstead