Cancer mutation may set off scleroderma

"As early cancers grow, the body is exposed to novel proteins caused by the mutations in the cancer and potentially opens a window to development of autoimmune disease," Bert Vogelstein says. (Credit: Quinn Dombrowski/Flickr)

A new study shows that cancer is a likely cause of scleroderma, an autoimmune disease that thickens and hardens skin, and causes widespread organ damage.

The findings, published in Science, also suggest that a normal immune system is critical for preventing common types of cancer.

“Our study results could change the way many physicians evaluate and eventually treat autoimmune diseases like scleroderma,” says Antony Rosen, director of rheumatology at Johns Hopkins University School of Medicine. “Current treatment strategies that are focused on dampening down the immune response in scleroderma could instead be replaced by strategies aimed at finding, diagnosing, and treating the underlying cancer.”


Rosen says his team’s findings should spur research into possible cancerous origins for other autoimmune diseases, including lupus and myositis.

The causes of autoimmune disease are largely unproven, Rosen says. Scientists have speculated that infections, chemical exposures, and inherited genes could be triggers, although hard evidence is lacking. None of those explains scleroderma, which is estimated to afflict as many as 300,000 Americans of all ages, but is not an inherited disease.

The immune systems of patients with scleroderma often make antibodies to a protein called RPC1. These antibodies are believed to cause the organ damage characteristic of the disease, but it has not been clear why the antibodies are produced.

Gene mutation

Rosen’s team has now demonstrated that cancers from a majority of patients with severe scleroderma have a mutation in a gene called POLR3A, responsible for producing RPC1. These alterations created a “foreign” form of the RPC1 protein, which they say appears to trigger an immune response. The study used blood and tumor tissue samples from 16 patients with scleroderma and different kinds of cancer.

Scientists knew that some patients with scleroderma have a higher incidence of cancer. In the most severe scleroderma, patients with antibodies against RPC1 develop cancers around the time of their diagnosis more frequently than patients who have other antibodies.


Rosen’s colleague and study co-investigator Kenneth Kinzler suspected that the POLR3A gene encoding RPC1 might contain mutations that trigger the development of cancer and scleroderma.

Kinzler and Bert Vogelstein, co-directors of the Ludwig Center, scanned the POLR3A gene’s DNA code in tumor samples from eight scleroderma patients with cancer and antibodies against RPC1. Tumors from six of the eight had genetic alterations in the POLR3A gene. All eight patients developed cancers between five months prior to their scleroderma diagnosis and two and a half years after it. The close timing of patients’ cancer and scleroderma diagnoses suggests that the two are linked, say the scientists.

“As early cancers grow, the body is exposed to novel proteins caused by the mutations in the cancer and potentially opens a window to development of autoimmune disease,” Vogelstein says.

The scientists found no POLR3A gene mutations in tumor samples from another eight scleroderma patients lacking antibodies against RPC1. These patients also developed cancers, but most long after their diagnosis with scleroderma, with half getting cancer more than 14 years later.

Study results may also help explain why, in some cases, people cured of cancer have also seen their scleroderma disappear.

“This study speaks to the power of the immune system and the emerging picture of harnessing the immune system to treat cancer, adding support to the notion that the immune system may be keeping cancers in check naturally,” says Kinzler, a professor of oncology at the Kimmel Cancer Center.

The National Institutes of Health, the Virginia and D. K. Ludwig Fund for Cancer Research, the Donald B. and Dorothy L. Stabler Foundation, the Scleroderma Research Foundation, and the Rheumatology Research Foundation Bridge Funding Award supported the study.

Source: Johns Hopkins University