Study Closes in on Cancer

Researchers at the Children’s Hospital Boston and the Harvard Immune Disease Institute have taken a step toward determining the mechanisms that govern the frequency and location of genetic mutations.

Their findings, published in the September 30 issue of Cell, could contribute to scientists’ understanding of cancer genomics and lead to future developments in gene therapy-based treatments for a wide range of diseases.

Cancerous genes are often the result of translocation mutations, in which parts of separate chromosomes physically break off and swap locations, forming "fusion" genes that encode for new, possibly cancerous functions.

But the rules governing the process remain unclear.

Led by Frederick W. Alt, professor of pediatrics at Harvard Medical School and director of the IDI, the team developed a method for mapping "hot spots" in the genome where chromosomes are most likely to break and recombine.

To do so, Alt and his colleagues developed a method called high-throughput genome-wide translocation sequencing (HTGTS), which is based on the action of DNA-cutting enzymes such as I-SceI.

Results revealed that broken chromosome segments are more likely to fuse near the beginning portions of genes, in areas called transcription start sites.

"The idea that transcription might cause breaks has been discussed for a long time, particularly from studies of bacteria and yeast," Alt said. "I think our paper shows rather conclusively that breaks do get generated widely by transcription and can indeed serve as substrates for translocation."

Alt said the next step in the research process is to determine the specific factors of transcription that cause chromosome breaks.

"There is more than one possibility," he said. "We are working on a potential collaboration with researchers from MIT to develop ways to approach the problem."

The potential impact of this research on the development of treatments for cancer and other conditions caused by gene mutation is multifaceted.

According to Alt, in its most plausible application, the research will contribute toward screening for tumors and possibly slowing their growth.

Monica Gostissa, a co-author of the paper and postdoctoral fellow working with Alt, added that the mapping technique could make it possible for researchers and companies cutting and using DNA to "better understand and prevent unwanted cuts."

While prenatal screening or diagnosis of diseases based on mapping chromosome "hot spots" is still far off, Alt said he is optimistic that the scientific community will eventually understand the rules controlling chromosome translocation.

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