Way back in 1994, a protein called p53 made it to the big time. It wascrowned molecule of the year, hailed as "Guardian of the Genome"and feted on the cover of a leading news magazine.

Since then, hundreds, if not thousands, of scientific papers havedescribed wild-type p53 as a genomic policeman, patrolling the cell-cycle checkpoint of dividing cells, to repair or discard those withfaulty DNA. In short, that good p53 cop was a tumor suppressor.

Named for its 53-kiloDalton mass, the normal 393-amino-acidprotein keeps healthy cells from over-replicating.

Contrariwise, the bad cop _ according to conventional wisdom _was a mutated p53, which couldn't arrest run-away cell division, andso triggered cancer. Thus, mutant p53 was an oncogene _ a tumorprogressor.

Now, like a promising theatrical job applicant with an exaggeratedresume, new evidence down-grades mutant p53 from a starring roleas instigator of malignancy to supporting actor at best, perhaps even amere extra.

This unexpected testimony takes the form of a report in next week'sJournal of the National Cancer Institute, dated Nov. 20, 1996. Itstitle: "p53 tumor suppressor gene status and the degree of genomicinstability in sporadic colorectal cancer."

The paper's senior author is molecular biologist Garth Anderson,who heads the department of molecular and cell biology at RoswellPark Cancer Institute in Buffalo, N.Y.

"A series of mutations must occur before a normal cell becomescancerous," Anderson pointed out. "Conventional wisdom said p53played the central role when gene systems ran amok. This is simplynot the case."

"Right now," the article's first author, surgical oncologist MortonKahlenberg, told BioWorld Today, "p53's prognostic value iscontroversial. There's a school of thought that believes: If you have apatient with a tumor containing a p53 mutation, that individual willhave a lower survival rate. An opposing school says p53 has no effectwhatsoever."

Kahlenberg is the paper's first author. "Hopefully," he said, "with ourlarge series of colorectal tumors we can help solve that controversy."

The Roswell team analyzed the presence of normal and mutant p53 inthe tumors of 58 patients, and compared their occurrence with theirgenomic instability. This is a standard measure of an individualtumor's proneness to progress.

p53 Cleared Of Genomic Instability Complicity

Kahlenberg explained: "Genomic instability reflects the propensityand susceptibility of a person's genome to acquire multiplealterations. These in turn are believed to be a driving force behindmultistep carcinogenesis."

He went on to point out that "there's a dilemma in linking p53mutation to this process. p53 mutation is thought to be a late event inthe development of sporadic colorectal tumors, whereas genomicinstability appears early in this progression."

He and Anderson base this observation on gauging the genomicinstability elevation of each of the 48 human tumors they studied. Todo so, they applied a PCR assay developed at Roswell Park.

Its starting point is scanning the 50,000 to 100,000 CA(cytosine/adenine) base-pair repeats scattered throughout the humangenome. Between these swaths of microsatellites occur the normalgenomic sequences of DNA.

"It's felt," Kahlenberg observed, "that regions near a CA repeat canbe more subject to alterations either with base-pair substitutions,insertions, deletions, DNA breakage, translocation of wholesequences, gene amplification _ whatever.

"In such regions, known as `hot spots,' " Kahlenberg pointed out,"the cells may be more unstable, and prone to carcinogenesis."

He and his co-authors identified p53 mutations in 29 of the 58 tumors_ 50 percent. Of the 29 with mutant p53, 19 had markedly lowgenomic instability scores.

Over-all, they determined that: "Tumors with no or minimal evidenceof genomic instability are more likely to harbor p53 mutations thantumors with evidence of substantial genomic instability." From thiscounter-intuitive finding, the team reached the conclusion: "p53mutations play an important role in the development of cancers, butdo not appear to initiate or promote genomic instability in sporadiccolorectal tumors.

Finding Seen As Eyebrow-Lifter

"So what we've actually shown," Kahlenberg summed up, "is theconverse of what most people in the p53 field actually felt to begoing on, which was that p53 was at the root of genomic instability .

"We certainly expect that this will raise some eyebrows," hecontinued. "It certainly raised some eyebrows here at Roswell amongpeople who are knowledgeable about p53. When I went ahead andamassed data. I made sure I was blinded _ as were the othermembers of our team looking at those gels for the instability values.But we went back and did everything in duplicate, and the resultswere sound scientifically. So we said: `OK, we have to go with whatwe have. Data are data.'"

Kahlenberg continued: We have to take our study one step further,and we're in the midst of doing that right now. We need to go back tothe clinical data base, and look at survival and disease-free survivalof these 58 patients. With that information in hand, see what theirp53 status was, and just as importantly, their genomic instabilityscores. See if those have any correlation whatsoever, with the ideathat the genomic instability value may have independent prognosticsignificance, as well as the p53 status."

That work in progress may have a pharmaceutical spin-off.

"There are a group of chemotherapeutic drugs," Kahlenberg noted,whose main function is to affect the cell cycle. We know that p53-mutated tumors sometimes have more chemoresistance. So the issueis going to be: Is it because their p53 mutated? Because such tumorshave a certain degree of genomic instability, and therefore are lesssensitive or more resistant to these anti-cancer drugs.

"That," he concluded, "could be the next step _ for an interestedgroup to go ahead and see if this genomic instability value has anyprognostic significance with chemotherapeutics." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.