Common gene found in most tumors Cell flaw called central to cancers

April 23, 1991|By Natalie Angier | Natalie Angier,New York Times News Service

All happy families are alike, said Leo Tolstoy, but every unhappy one is unhappy in its own way.

Not so for the cells of the human body. A healthy liver cell looks and acts very differently from a well-behaved constituent of the breast, bladder, brain or lung.

But scientists are finding that at the core of nearly every type of tumor cell, whatever the organ of origin, lies the same terrible flaw.

The flaw afflicts a single gene in the cell, a gene that goes by the humdrum name of p53. So nearly universal is the defect in human tumors that scientists are beginning to suspect that it could be an almost indispensable step in cancerous transformation.

Other genes clearly are mutated in any given cancer. But while some mutations vary from one class of tumor to the next, a blow to the p53gene could be a common denominator to nearly every malignancy, particularly the most prevalent and deadliest adult tumors.

Scientists believe that in its normal state the gene must be central to cellular harmony and that before a cell can descend into complete chaos, its p53 gene must be corrupted.

"This quite clearly is the most commonly mutated gene we've yet found in human cancers," said Dr. Bert Vogelstein of the Johns Hopkins School of Medicine. "The list of tumors that are affected is fairly staggering, and on that basis alone the work is extremely important."

The gene is mutated in a huge percentage of malignancies of the lung, breast, colon, skin, blood, throat, brain and liver.

The new research is lofting the gene from its previous position as a sideline oddity in cancer biology to the sole focus of research in top-flight laboratories.

Scientists are fleshing out a portrait of the gene that is more sophisticated and finely detailed than that for any of the other 50 to 60 genes implicated in various kinds of cancers. And they are finding that the mutant p53 gene behaves as no other known cancer gene does.

call it a Jekyll and Hyde gene," said Dr. Curtis C. Harris of the National Cancer Institute in Bethesda. "Once it's mutated, it not only loses its original personality, it takes on new powers it never had before."

In a string of recent papers about p53, researchers have identified regions of the gene that are molecular "hot spots," fragile sites where carcinogens from the environment are likely to attack and destroy.

Several weeks ago, scientists linked one tiny mutation in the gene to biochemical harm from aflatoxin, a potent carcinogen found in moldy food and a suspected cause of liver cancer in parts of Africa and China.

Other scientists are on the verge of making a similar connection between another type of p53 mutation and the hazardous byproducts of fatty foods.

But damage from the outside is not the only way to disrupt the gene. Dr. Stephen H. Friend of Massachusetts General Hospital in Boston and his colleagues have discovered that some people are born with mutant versions of the p53 gene, meaning that every cell of the body is burdened with the mutation.

Such people have been found to have an extraordinarily high chance of contracting breast cancer and at least six other types of tumors. Scientists are trying to determine how common the germline defect is.

The researchers are not yet prepared to say how many breast cancer patients carry the defect, beyond indicating that it is not likely to exceed 5 percent. But that figure could be high enough, they say, to considerscreening all breast cancer patients for the presence of a germline flaw.

Other patients thought to be possible carriers of the inborn p53 mutation include women who suffer from both breast and uterine cancer, and people who are successfully treated for one type of tumor, only to fall prey to a very different malignancy later.

At the moment, checking a patient's DNA for mutant p53 is an involved and prohibitively expensive procedure. But scientists are perfecting a method for detecting mutant p53 genes in a simple blood test.

People found to have the genetic flaw might consider more frequent mammograms, said researchers, or the use of experimental therapies such as tamoxifen, which could help prevent breast cancer.

And because any person carrying the gene would have a 50 percent chance of passing along the defect to a child, the test could prove valuable for prenatal diagnosis.

Scientists said that impairment of the p53 gene, whether inborn or resulting from poisons in the environment, is not enough to foster cancer.

At least four or five other genes must be derailed as well. But the loss of a working p53 gene can spell the difference between a tiny cluster of pre-cancerous cells that grows at a desultory and non-threatening rate, and a full-blown, angry tumor.

"In some cases, p53 seems to act as the cell's emergency brake," said Dr. Vogelstein. "After other parts of the cell have broken down, the cell relies on p53 as a last way to keep it in check."

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