By David N. Leff

A news item in BioWorld Today in January triggered a publish-or-perish sprint between two rival research groups. It climaxed in today's Science, dated March 28, 1997, and in the April issue of Nature Genetics.

When Cold Spring Harbor molecular biologist Michael Wigler read the Jan. 23, 1997 BioWorld Today article headlined "Myriad Genetics Identifies Deadly Brain Cancer Gene," he felt suddenly blindsided. Wigler quickly phoned his collaborator, Columbia University molecular biologist Ramon Parsons.

As reported by Science Elizabeth Pennisi, ". . . when the [Myriad] release was mentioned in the biotech newsletter BioWorld, it . . . alerted Parsons to the competition at Myriad."

Myriad Genetics Inc., of Salt Lake City, is teamed with M.D. Anderson Cancer Center, of Houston, in hot pursuit of a tumor suppressor gene gone wrong. So is the Parsons-Wigler partnership. Until the BioWorld Today news break in January, neither group knew that the other had discovered the same tumorigenic mutant gene.

Both then dashed to get their account into print.

In a photo finish, Wigler and Parsons made it to today's Science, with a paper titled "PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast and prostate cancer."

Myriad's cancer research director, Sean Tavtigian, with M. D. Anderson's Peter Steck, got their competing version into Nature Genetics, headed: "Identification of a candidate tumor suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers." (The journal moved up its embargo date, for this article only, to match that of Science.)

Parsons' PTEN sequence, standing for "phosphatase and tensin homologue deleted on chromosome 10," and Myriad's MMAC1 gene, "mutated in multiple advanced cancers," turn out to be one and the same, both located at the same site on the long arm of human chromosome 10.

By whichever name, both groups report that the mutated gene's inactivated product occurs at very high frequency in a particularly vicious brain tumor, glioblastoma multiforme (GBM).

"This brain cancer is very aggressive," said neuro-oncologist Steck, "and our research suggests that mutations in the MMAC1 gene play a role in advancing the aggressiveness of the tumor. The discovery," he added, "will extend our understanding of this process not only in GBM, but also in several other solid tumors such as prostate, breast, kidney and skin."

Brain Cancer Only One Of Mutant Genes' Targets

GBM is the commonest primary tumor of the central nervous system, and the commonest solid tumor in children. Each year in the U.S., 19,000 new primary brain cancers are diagnosed, and this incidence is on the rise. Between 5,000 and 6,000 Americans die each year of GBM. Steck and Tavtigian found that six out of six GBM tumors they analyzed contained mutated copies of their presumed MMAC1 gene. It also turned up in a high proportion of other cancers, notably prostate.

Parsons told BioWorld Today: "There is some evidence to suggest that loss of P-TEN, the protein expressed by the PTEN gene, affects the way a less advanced tumor becomes more aggressive. We identified 20 mutations of PTEN in advanced brain, breast and prostate cancers. Based on our finding," he added, "it may some day be possible to test people for mutations of PTEN, which would give an early warning of cancer danger."

Richard Klausner, director of the National Cancer Institute, had this to say: "This discovery represents one of the first genes to be implicated in aggressive and generally fatal brain tumors, a type of cancer in which we desperately need clues that the PTEN gene may offer."

In its native, unmutated form, the twice-named gene product is a candidate for election to the select roster of some 16 tumor suppressors, perhaps in the same league as the p53, p16 and retinoblastoma genes. All three are mutated in GBM.

"But the most common genetic alteration," Tavtigian told BioWorld Today, "is the deletion of large regions, or an entire copy, of chromosome 10. That locus on the chromosome's long arm is also a hot spot for prostate, kidney, lung, melanoma and other solid tumors, suggesting the existence of one or more tumor-suppressor loci."

"Both new genes' location on chromosome 10," Parsons said, "suggests implication in sporadic rather than inherited cancers, which account for about 80 percent of all malignancies.

"It's very exciting that they are potential phosphatases," he went on. "Actually, the very first oncogene ever found is a phosphatase kinase, which adds phosphates to proteins in a gene known as sarc. It was discovered by Peyton Rous near the turn of the century. And all this time, people haven't thought about looking for a tyrosine phosphate tumor suppressor gene. These are the first ones."

To check on MMACI gene mutations, Tavtigian and Steck looked at DNA samples from a series of solid tumors. At that chromosome 10 spot they found deletions in 40 of 53 (75 percent) gliomas, one of 10 melanomas (10 percent), 30 of 89 (34 percent) breast and four of 10 (40 percent) kidney cancers.

Parsons' and Wigler's data in Science was strikingly similar:

In tumor cell lines, they detected deletions or nonsense PTEN mutations in five out of eight (63 percent) glioblastomas, four of four (100 percent) prostate cancers and two of 20 (10 percent) breast, but suggested "these frequencies are likely to be underestimates."

First Steps Under Way Toward Drug Discovery

Topping Parsons' present agenda, he said, "is to correlate information on patients about their clinical outcomes with whether the TPEN mutation is present or absent. Another thing we want to do," he added, "is to study the function of the gene by putting it back into cells that are missing it, and see how that affects the behavior of tumors."

Parsons continued: "We also need to understand the potential kinase that's actually antagonizing PTEN, which is the 'go' signal for tumor progression, because it would be great to develop drugs to inhibit that enzyme. We don't have that yet, but it does open a window in which we can start exploring for developing these new drugs."

In a similar vein, Myriad's Tavtigian observed, "Where we stand right now is, we're searching for the substrate and the kinases. When those are identified, we'll need to develop small molecules that would inhibit the kinase.

"The other thing," he concluded, "is that there is always the possibility that gene therapy might work. In which case, we would want to replace the function of MMAC1 by the gene therapy approach." *

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