By David N. Leff
A person can go through life quite comfortably with only one kidney. Like eyes, lungs, ovaries, testicles and other paired organs, kidneys are designed for redundancy.
"You can do fine with a single kidney," observed molecular biologist Glenn Evans of the University of Texas Southwestern Medical Center, in Dallas, "but you have no backup."
He was citing this stark fact to evoke a similar situation at the microscopic level of the human genome. Of its 46 chromosomes, 44 are paired, one each donated by each of an individual's parents.
Often, one parent will bequeath to his or her offspring a chromosome carrying one or more defective genes, linked to a disease syndrome. As happens with the carrier of a single kidney, this chromosomal imbalance leaves the recipient offspring with no backup, should the intact chromosome somehow fail. In genetic terms, that person is heterozygotic for that trait.
"If a mutation occurs in one of those two parental genes," Evans pointed out, "it may not have any effect. It sits there for years, like a little time bomb."
But, should some mutation befall the same gene in the intact chromosome, it detonates the bomb. The victim suffers loss of heterozygosity (LOH), and faces the dire consequences of homozygosity — frequently cancer.
"All that has to happen," Evans explained, "is when the other gene is inactivated, cancer starts. For some reason, a big chunk of the chromosome in one cell of an organ's tissue disappears, and that's sufficient to turn off both copies of the gene, so that the cell begins growing and dividing uncontrollably."
Evans is senior author of a paper in today's Science, dated Oct. 9, 1998, titled: "Alterations of the PPP2R1B gene in human lung and colon cancer."
"PPP2R1B," he explained, "is a gene that's very important for the normal regulation of the cell. And when there are no mutations in it, it acts as a tumor-suppressor gene. That means a gene where, when both of its two copies are inactivated, cancer occurs.
"LOH is a clue or hallmark for tumor suppressor genes," Evans continued. "Many of the most important genomic hot spots — the big ones involved in lots of cancers — can be seen by this phenomenon of LOH, but haven't been discovered yet. What the LOH does," he went on, "is turn the gene off. Because a tumor-suppressor gene's action requires both of the two genes to be inactivated, it too is turned off, and cancer kicks in."
Scoping Three Risk Factors
To ask what precipitates this loss of heterozygosity is to ask what causes cancer. Evans suggests three factors: chance, heredity and toxins.
"A variety of things can lead to those mutations in the genes," he observed. Some of them are spontaneous — no known reason. We believe that, in the case of the PPP2R1B gene, some of the defects are actually inherited from the parent, meaning that there may be individuals with an inherited predisposition to get cancer, and much more likely to get it at a young age than others.
"The final risk factors," Evans went on, "are toxins, like cigarette smoke in lung cancers. It's well known that the mechanism of this PPP2R1B gene is very sensitive to chemicals. There's a chemical called okadaic acid," he continued. "It's one of the toxins in cigarette smoke. And it's well known that this one inhibits phosphatase activity, which controls how cell growth is regulated. That is, the toxin shuts down the gene the same way mutations do."
Steven Wang, a post-doctoral fellow in Evans' lab, is the Science paper's lead author. He began analyzing hundreds of human lung tumor cell lines. He found that this gene was active, and also narrowed its location down to a very small interval — about a million base pairs long — on the long arm of chromosome 11.
"The entire human genome," Evans pointed out, "is three billion, so it's quite a small region compared with the whole."
The co-authors found quite a number of mutations in both lung and colon tumor cell lines.
"While we haven't actually proven it yet," Evans said, "it's very likely that there are mutations in other cancers as well — breast, cervical, head and neck, to name a few. This is work that's going on now in my lab."
Clinical Payoffs 'Imminent'
Evans foresees early application of these findings in prediction, diagnosis and treatment of cancer:
"For diagnostics, it tells us that any inherited changes in this gene would be likely to predispose the individuals for lung or colon cancer. We know," he observed, "that some people can smoke all their lives, be 95 years old and never develop lung cancer. Other people acquire this inheritance at a very young age. It is possible that would allow us to develop a test to determine who is at risk and who is not for lung, colon or other kinds of cancer. That's the diagnostic aspect of it.
"The therapeutic aspect," Evans continued, "is unlike many of these gene-hunting stories, where one finds the gene and then scratches one's head and asks: 'What the heck does this do? What do we do about it?' In this case, we know precisely what it does, and it gives us an excellent idea of what we have to do about it.
"What we have to do," he said, "is change the regulation of phosphate on the critical proteins the gene expresses. Since, in the cancer, this gene is shut off, if we could put an active one back in, we know it would reverse the tumor. So, it creates the possibility of gene therapy, or even [the possibility of] developing drugs that would affect that phosphorylation pathway.
"It's very likely that this gene system can be used as an assay for drug discovery, and that knowing this information will allow big companies or small companies to start screening compounds — there's millions of compounds they've already made — for activity in this phosphate pathway," Evans concluded. "So, I think it will be imminent." *