CHD5: master switch for suppressing tumo

[eric]

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Team's Breakthrough Gene Discovery in Cancer Research

An Indian American scientist is part of a team that has announced a breakthrough in cancer research that has led to the discovery of a critical gene and revealed a master switch for suppressing the growth of tumors.

Anindya Bagchi, the lead author of an article that published the findings of the study led by Prof. Alea Mills of New York's Cold Spring Harbor Laboratory, told India-West: "It has a huge potential for therapeutic application in the future.

"In the cancer biology field...this is something we have identified that people have been looking for decades now - 30 years." The study was published in the February issue of the journal Cell.

"We not only found a critical tumor suppressor gene, but have revealed a master switch for a tumor suppressive network that means more targeted and effective cancer therapy in the future," said Mills.

Mills commended Bagchi's role in the research. "I first met Anindya (Bagchi) at a meeting in the U.K....Anindya and I talked at length about things we might learn by altering chromosomes - the technology was amazing. Even though Anindya was only a student at the time, it was clear that this was a guy with guts - just the type of person that I wanted as part of my research team."

The discovery has been hailed by cancer experts nationwide.

Dr. Pier Paolo Pandolfi, a cancer biology expert with the Memorial Sloan-Kettering Cancer Center in New York, told the New York newspaper The Daily News that the Cold Spring Harbor discovery is critical - and very important.

Pandolfi's laboratory discovered another master switch, reported in 2005, a gene dubbed Pokemon after misbehaving electronic-game characters.

"They found a good cop - a tumor suppressor gene," Pandolfi said of the Cold Spring Harbor team. "We found a bad cop, an oncogene." Oncogenes cause normal cells to become cancerous and arrest their death.

For decades, scientists have known that many cancers have a signature genetic anomaly - a section of one chromosome is missing. Specifically, a region called 1p36 is often deleted. This caused cancer scientists to reason that this section of the chromosome contained an important gene, that when lost, leads to cancer.

However, the identity of this tumor suppressor gene remained elusive for three decades.

"There had been a very important question in cancer biology that whether there is a gene out there that might be regulating or preventing us from having cancer," Bagchi said.

"There are multiple genes out there in that region (of the chromosome) and people tried to map which is the particular gene that might be responsible for preventing this multiple kind of cancer because many of the patients, when they lose this chunk of DNA containing multiple genes, they are predisposed to cancer."

The CSHL discovery is based on a cutting-edge technology devised in 1995 by a team of researchers led by Dr. Allan Bradley, then with Houston's Baylor College of Medicine, called chromosome engineering technology, where "he can clip out portions of DNA in the mouse embryonic stem cells and therefore he can mimic the conditions we can see in human patients," Bagchi explained to India-West.

Mills subsequently improved on the technology to further the search for the elusive gene.

"Human and mouse genome are about 90 percent similar," Bagchi said. "The piece of DNA that is missing in human DNA cancer, we can map the identical region in mouse chromosome and we can use this technology to snip that part out.

"But also the beauty of this technology is you can snip out and you can add. There is what we call loss of function as well as gain of function, (and) we can make two different models.

"So we started scanning that part of the area of mouse genome, which is similar to human 1p36 that's the map of the region, it's a big region. We started scanning that region by taking out small pieces of that region and we hung on there for a very long time."

CSHL researchers found that when mice lose the portion of the chromosome that includes the CHD5 gene, they develop tumors. On the other hand, when mice have an extra copy of the same region, they have extra tumor suppressive activity. Indeed, the human version of this gene, CHD5, is frequently deleted in glioblastoma - a type of brain cancer.

Bagchi said they hit the right region around late 2005. "After that we hit upon a few other key results by middle of 2006 and everything started falling in its place."

Stanford University researchers Hannes Vogel and Markus Bredel have independently verified the result of the CSHL study in the human context, Bagchi added.

Bagchi said it was the combined teamwork of many that had brought about the result.

"When we solved the problem, all pieces of the puzzle suddenly fell into place - it appeared so simple! Dr. Mills led a great team; the contributions of (CSHL researchers) Cristian Papazoglu and Ying Wu, as well as (Stanford researchers) Hannes Vogel and Markus Bredel made this study complete. For me, the lesson that I learned is simply this: Ideas win!"

This breakthrough research and discovery was funded largely by private sector donations. Cold Spring Harbor Laboratory, a private, non-profit basic research and educational institution, is one of eight National Cancer Institute-designated basic research centers in the U.S.