Wake Forest-Johns Hopkins team discovers prostate cancer gene

Scientists in the Center for Human Genomics at Wake Forest University School of Medicine and Johns Hopkins Medical Institutions have discovered a gene that “may play an important role in prostate cancer susceptibility in both African-American men and men of European descent.”

The 31-member team reports in the October issue of Nature Genetics that mutations in the MSR1 (for Macrophage Scavenger Receptor 1) gene were found in 4.4 percent of Caucasians who had prostate cancer, compared to 0.8 percent who were found to be unaffected following prostate cancer screening. A different mutation of the gene was found in 12.5 percent of African-American men with prostate cancer, compared to 1.82 percent of unaffected men.

Both differences are highly significant statistically. “One of the mutations leads to prostate cancer that has rapid metastasis,” said Jianfeng Xu, M.D., Dr. P.H., associate professor of both public health sciences (epidemiology) and cancer biology at Wake Forest.

Prostate cancer is the most common cancer in men, with more than 300,000 new cases diagnosed annually. The highest risk and the greatest mortality is among African-Americans.

Xu, Deborah A. Meyers, Ph.D., professor of pediatrics (medical genetics), S. Lilly Zheng, M.D., research assistant professor of internal medicine (pulmonary), and nine other Wake Forest researchers, said in their report, “We provide novel genetic evidence that MSR1 may play an important role in prostate cancer susceptibility.” MSR1 was already known for its role in hardening of the arteries.

They said they had found seven potentially important mutations of the MSR1 gene — including the rapidly metastasizing form that truncates (and makes dysfunctional) the MSR1 protein — in families with hereditary prostate cancer. “Importantly, they were either not observed or observed less frequently in men without prostate cancer,” they reported.

Just as there are a number of breast cancer genes, the MSR1 gene probably will turn out to be one of a number of genes linked to prostate cancer. However, MSR1 appears to be the strongest gene linked to inherited prostate cancer risk thus far, they said.

Working with William B. Isaacs, Ph.D., Patrick C. Walsh, M.D., and others at Johns Hopkins, the research team evaluated the role of MSR1 in a large number of subjects from multiple populations. They began with 159 patients from families that averaged five or more men with prostate cancer, evaluating samples of their DNA to look at the MSR1 gene, and they found eight mutations. They sought samples from all family members of these 159 patients.

Seven mutations were rare, showing up in a total of 13 families. Six of those families — all of European descent — had the rapidly metastasizing one they called Arg293X. Another four families, all African-Americans, had a variant called D174Y; five mutations were found in one family each. The eighth, a common variant, P275A, was found in 30 of the 159 families. Using various statistical analyses, they found links between these mutations and prostate cancer. Xu and Meyers began looking for other groups in the general population that had already been studied for other diseases, adding analysis of variants of the MSR1 gene. They looked at a group of 518 men who were studied for asbestos exposure, regardless of their prostate cancer status. They found the Arg293X variant seven times among 469 men of European descent.

“Interestingly, two of these carriers were among the 28 men in this group diagnosed with prostate cancer,” they said.

When they analyzed 49 African-Americans in the asbestos study, they found two with the D174Y variant they already were tracking in their hereditary prostate cancer families; one of the two already had a high normal PSA test.

Since the gene is on a macrophage scavenger — a white blood cell that goes after bacteria, cell fragments and even whole diseased cells –the Johns Hopkins team is studying the relationship between MSR1 and inflammation. They have data that suggests macrophages carrying variants in the MSR1 gene may not be able to fight infections as well as non-affected macrophages. That may explain the already suggested link between infection and prostate cancer.