NEWS

Do Autoimmune Diseases Raise The Risk of Cancer?

Nancy Volkers

Is there a link buried in the immune system between autoimmune disease, when the body mistakenly turns on itself, and cancer, when the body should attack itself, but does not?

Although several studies have shown that a history of autoimmune disease increases the risk of cancer, the results are complicated by the fact that some treatments for common conditions, such as lupus and rheumatoid arthritis, also may increase this risk.

A registry linkage study published in 1998 found that lupus patients — who are mostly women — have a twofold risk of cancer compared with people who do not have lupus. A 1997 study in Shanghai, China, found a 2.4-fold excess risk of esophageal cancer in patients with a history of autoimmune diseases. And an earlier study, using the same data, found that a prior history of autoimmune disease was associated with a twofold increased risk of pancreatic cancer.

Meanwhile, a 1993 study at the University of Toronto found that patients with systemic sclerosis have a twofold risk of cancer, and a study from the Medical College of Wisconsin found that systemic sclerosis elevated risks for lung cancer (fivefold), liver cancer (threefold), and nonmelanoma skin cancer (fourfold).

At the University of Ioannina, Greece, researchers went even further — their 1995 study found an increased risk of cancer in first-degree relatives of patients with systemic sclerosis.

Results such as these don't necessarily point to genetics, said Glinda Cooper, Ph.D., investigator in the epidemiology branch of the National Institute of Environmental Health Sciences, Research Triangle Park, N.C. "If you do see a familial association, there's a tendency to attribute it to genetics," she said, "but that's not the case — it may be a common exposure. You could certainly speculate about different reasons" for the association.

Cooper leads the Carolina Lupus Study, a case-control study of newly diagnosed lupus patients that focuses on a broad array of exposures and family histories of several diseases, including cancer.

"Lupus patients do have an increased risk of cancer - that's not an issue," said Cooper. "This is: If you have lupus, do your family members have an increased risk of cancer?"

GSTs — a Link?

The revolution in molecular biology has thrown the doors wide open to research linking autoimmune disorders and cancer. Of particular interest may be the glutathione S-transferases, or GSTs, a family of genes coding for enzymes that help metabolize potentially toxic compounds. Research on GSTs shows they are key players, not only in many types of cancer, but also in disorders such as lupus, rheumatoid arthritis, and myelodysplastic syndrome.

GST mu and GST theta are two of the most widely studied genes. "The mu and theta genes are interesting because 20% to 50% of the population doesn't have them; one or both is missing," said Timothy R. Rebbeck, Ph.D., associate professor of epidemiology at the University of Pennsylvania, Philadelphia. "That identifies a pretty clear set of people who might be at risk, because they can't metabolize through these pathways."



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Dr. Timothy R. Rebbeck

 
Rebbeck and colleagues have been studying GST genotypes and the risk of prostate cancer. In a study published earlier this year, they found a seemingly paradoxical result: men with GSTT1 (theta-1) genotypes had a nearly twofold increased risk of prostate cancer, compared with men who were missing this gene.

"We found that if you have a GST, as opposed to having it missing, you're at risk [for cancer]," said Rebbeck. "We spent a lot of time thinking that that was just wrong, because it was opposite to the hypotheses. GST metabolism experts told us: if [the gene is] there, it's getting rid of carcinogens, and if it's not, it's not."

The story, however, is more complicated. "What happens in metabolism is that byproducts form," said Rebbeck. "The GSTs can form products that are damaging to cells . . . it's not just the deletion that might be associated with cancer, but it might be the presence of the gene that causes metabolism and thus a problem."

GSTs have also been implicated in breast cancer. A study by Johns Hopkins researchers found that women lacking the GSTM1 gene had a twofold increased risk of breast cancer, and women lacking the GSTT1 gene had a 1.5-fold increased risk. Women lacking both genes had a nearly fourfold risk.

"The piece we'd like to put into the puzzle is what are the environmental factors involved," said Kathy Helzlsouer, M.D., professor of epidemiology at the Johns Hopkins School of Public Health. "Everyone talks about the gene-environment interaction, but they tend to concentrate on the gene."

On the autoimmune disorder front, studies in the United Kingdom have associated certain GST genotypes with lupus, rheumatoid arthritis, basal cell carcinoma, colorectal cancer, and acute lymphocytic leukemia. Richard Strange, Ph.D., professor of clinical biochemistry, Keele University, Staffordshire, England, has published widely in this area.



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Dr. Richard Strange

 
"How is it that a group of genes are cropping up in all these different diseases — how do we rationalize that?" he asked. "I think the link comes in oxidative stress. So many genes are expressed or not, depending on the level of physiological stress."

Another gene important to potential links between autoimmune disorders and cancer is PTEN, a tumor suppressor gene that is one of a number of genes that help induce apoptosis in flawed cells. Until recently, it was thought that both copies of the PTEN gene must be lost or mutated for cancer to result.

However, a September article published in Science showed that in mice, the loss of just one PTEN gene was enough to stop apoptosis and allow cancer growth.

In an interesting twist, loss of one PTEN gene also caused lymphocytes to accumulate, attack organs, and eventually kill many mice in a disease process similar to that of lupus.

Pier Paolo Pandolfi, M.D., Ph.D., was lead author of the study and is head of the Laboratory of Molecular and Developmental Biology in the Department of Human Genetics at the Memorial Sloan-Kettering Cancer Center, New York.

"The dogma in cancer genetics is that you have to lose both alleles of a tumor suppressor gene," said Pandolfi.

"Here we really challenge the dogma because we find that when you have one allele mutated, you are at risk. You already impair programmed cell death."

As for the connection between cancer and autoimmunity, said Pandolfi, "This is possibly one of the most convincing examples [of a cancer-immune disorder connection] in mice, but we have to be cautious that we don't extrapolate [to] humans."

However, all cells of the experimental mice contained an inactivated PTEN gene, he explained, whereas in humans this would not be the case.


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