Scientists at the University of Michigan Medical Center have recently devised a new method to uncover dangerous "gene fusions" that can lead to cancer. The identification of these new genetic errors may lead to new targeted cancer treatments.

When a gene is turned on, it generates a message or "transcript," giving the cell instructions to make a particular protein. Occasionally, DNA damage can cause two genes that are normally separate to be placed next to each other. The resulting gene fusion can produce a dangerous protein that behaves differently than either of the original proteins. The fusion protein could be turned on at the wrong time, or all the time, causing cells to grow and divide when they shouldn't. At any given time, thousands of different genes in a cell are turned on, and thousands of transcripts are being made and relaying their messages. The Michigan researchers reasoned that genes that cause cancer are likely to be turned on, so they sequenced all of the transcripts in a tumor cell line, known together as the "transcriptome." Their results are published in the journal Nature.

The researchers initially directed their efforts at a proof-of-principle experiment, in which they used their technique to rediscover an already known gene fusion, BCR-ABL. BCR-ABL is a fusion of two genes that results from DNA damage causing pieces of chromosomes to trade places, or "translocate." The resulting fusion of these two different chromosomes is called the "Philadelphia Chromosome." BCR-ABL is commonly found in chronic myelogenous leukemia, and is the target for Gleevec, a very successful leukemia drug and one of the early molecular targeted drugs. Using an approach that included both long and short sequencing "reads," the scientists successfully rediscovered BCR-ABL.

The scientists next turned to prostate cancer cells, where they reidentified a previously known gene fusion called TMPRSS2-ERG. In addition, they discovered several new gene fusions. One of these fusions involves the gene GPSN2, which is involved in the production of dihydrotestosterone, a prostate cancer therapeutic target. Another novel fusion involved the gene SLC45A3, which is specific to the prostate and has been reported to be involved in another fusion in a different prostate cancer sample. The scientists verified all the new fusions by independent methods. The verified fusions are expressed in prostate cancer cells, but not in healthy cells.

Interestingly, one of the fusions, called SLC45A3-ELK4 is a "read-through"—a fusion of two adjacent genes. This fusion is only detectable using the transcript sequencing method used by the authors of this study; techniques that sequence or examine the genomic DNA would never uncover this type of gene fusion. SLC45A3-ELK4 is the first example of a cancer-causing genetic lesion that is present only at the level of the transcript or RNA, rather than the underlying DNA.

The technique used in this study represents a valuable new tool for detecting cancer-causing genetic aberrations. The new fusions identified by this technique represent new potential diagnostic markers and targets for molecular therapy.
— Sheryl Krevsky Elkin

Reference:
Maher, CA, Kumar-Sinha, C, Cao, X, Kalyana-Sundaram, S, Han, B, Jing, X, Sam, L, Barrette, T, Palanisamy, N, and Chinnaiyan, AM. (2009) Transcriptome sequencing to detect gene fusions in cancer. Nature Jan 11. [Epub ahead of print]. Abstract.