By David N. Leff

Consider the People's Republic of China: Its population, by latest figures, numbers 1,210,004,956 — nearly five times that of the U.S. at 264.6 million.

Now consider cancer: In mainland China, the death rate from neoplastic diseases stands at 148.2 per 100,000, according to U.S. National Cancer Institute (NCI) statistics. That works out to 1,482 deaths per million, or some 1,793,220 of the population per year.

Next, consider nasopharyngeal carcinoma (NPC), which is endemic throughout South China, including Hong Kong. An estimated 20 percent of all cancers in China are NPC. Which doesn't mean, of course, that all the victimes die of it, but gives an idea of this particular malignancy's importance in that country.

Finally, fast forward to the U.S. Four percent of its people are of Asian origin. In 1995, 816,000 of these were Chinese.

What about nasopharyngeal carcinoma among Americans? It amounts to 0.25 percent of all cancers in North America. But among the Chinese cohort, NPC scores 20 percent.

Only 3 percent of U.S. patients have distant metastases at diagnosis of NPC; the rate is much higher in China.

Incidentally, NPC also occurs in North Africa, and among Greenland's Inuit families. But it's almost unknown among the world's whites and blacks.

All these data point strongly to a familial genetic component in the etiology of nasopharyngeal carcinoma.

Investigators Worldwide Gang Up On NPC

The nasopharynx lies behind the nose and upper throat (the pharynx). It is a tube about five inches long that starts behind the nose and goes down the neck to join the esophagus. En route, two openings lead into the ears. The two nostrils form the vestibule to the pharynx. All these epithelial surfaces are targets for squamous cell carcinoma to take root.

A lump growing in the nose or neck is the main symptom that brings NPC patients into the clinic. Other early complaints include hearing loss, ringing in the ears, profuse nosebleeds, nasal obstruction, headache, even halitosis. As in other cancers, treatment features surgery and radiation, chemotherapy, and for advanced cases, a clinical trial of combination regimens.

Besides Asian ancestry, other much-explored risk factors range from Epstein-Barr virus to excessive tobacco and alcohol use (recently discounted) to a diet top-heavy in salted fish. What seems clear is that when South Chinese people migrate to another continent (such as North America), they bring with them a predisposition to contract nasopharyngeal carcinoma.

A research paper in the current Proceedings of the National Academy of Sciences (PNAS), dated March 17, 1998, dispels some of the puzzlement over NPC's hereditary component. Its title: "Functional evidence for a nasopharyngeal carcinoma tumor suppressor gene that maps at chromosome 3p21.3."

The article's co-authorship represents an international research consortium dedicated to unmasking NPC's mysteries, with collaborators from the People's Republic of China, including Hong Kong; the NCI, in Frederick, Md.; Genos Biosciences Inc., of La Jolla, Calif.; and its senior author, microbiologist Eric Stanbridge, of the University of California at Irvine.

George Klein, an Epstein-Barr virologist at Sweden's Karolinska Institute and a member of the U.S. National Academy of Sciences, submitted the paper to PNAS.

"This particular paper," said molecular geneticist Michael Lerman, of NCI, "shows that this is probably the same gene that is involved in lung cancer. I would prefer to say causing lung cancer. Sometimes I call it 'LuCa,' for lung cancer."

Lerman directs a seven-person section at NCI that concentrates on tumor suppressor genes on the short arm of human chromosome 3.

"One of them," he told BioWorld Today, "is the 3p21.3. Another gene, which I'm also cloning in collaboration with a British group in Cambridge, U.K., and one in Dallas, is located more proximally at 3p12."

The consortium tracked the PNAS gene to its genomic neighborhood on chromosome 3 by deletion mapping, Lerman recounted. Its starting material consisted of human lung cancer cell lines. The mapping implicated NPC as well.

Once cloned, the gene's tumor-related function will become clear, Lerman observed. "As a tumor suppressor gene, its mutation will cause LuCa, and presumably NPC, by being absent from the tumor cells; that is, by loss of function.

"It's been known for a long time," he pointed out, "that cancer is a genetic disease, and a multistep disease. This means that tumor genes are, one by one, either destroyed or activated by mutations. And this results in a phenotype described as progression of disease."

He continued: "Translated into genetic terminology, I believe that in NPC, it would account for three or four genes, one causative — which initiates the cancer — the rest just involved in tumor development."

Reversing Mutant NPC Gene's Tumorigenicity

As described in the PNAS paper, Lerman went on, "a normal chromosome 3 was transferred into an NPC cell line called HONE1, which stands for Hong Kong. This experiment," he explained, "tested the possibility that tumor suppressing activity can be restored to HONE1 via transfer of a normal chromosome 3. And this in fact is what happened.

"After that, we and other collaborators grew those cells, put them into nude mice, and registered tumor formation. Eric Stanbridge and others," he added, "have already established chromosomes with deletions. So you can see which region is necessary for biological activity in tumor formation."

NPC, Lerman explained, "is a squamous cell carcinoma of epithelial cells. Quite a lot of people suffer from this disease, which has a wider importance because the same gene mutant that we suppose causes lung cancer is apparently involved in familial NPC, too."

He and other co-authors are now "planning to go on and test different candidate genes which we have identified in the 3p region, and again transfer them to cells, then to nude mice.

As for putative payoffs down the road in the clinic, Lerman opined: "If you clone the gene — right? — my personal opinion is that only various gene therapy applications could be of use here. Of course," he concluded, "we can then analyze NPC by biochemistry; we can make antibodies; we can make thousands of things." *

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