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Researchers Discover Potential Functional Role of Genetic Variation in Prostate Cancer Risk

Researchers have described how a common genetic variation may be involved in the development of prostate cancer. The variant occurs in a gene known to be involved in prostate function. The study, which included a team of researchers at the National Cancer Institute (NCI), part of the National Institutes of Health, uncovered how a small change in the DNA of the gene impacts the biology of prostate cancer risk. The study was published online April 20, 2009, in Proceedings of the National Academy of Sciences.

Differences in the sequence of DNA among individuals are called genetic variations, and some known variations have been associated with an increased risk of certain diseases, such as prostate cancer. The most common type of genetic variation is a change in a single nucleotide, or base, which is one of the building blocks of DNA. Such single-nucleotide polymorphisms (SNPs) are used in genome-wide association studies of large numbers of individuals with and without a disease to identify DNA regions that are associated with the disease. Although previous studies have identified regions of the genome that are associated with prostate cancer risk, this study was one of the first to explain the biological mechanism underlying the difference in risk among individuals.

Recently, two independent genome-wide association studies of chromosomal regions associated with prostate cancer risk identified a SNP located in a region of chromosome 10 that plays a role in the expression of the gene MSMB. This gene produces a protein that is a potential biomarker for prostate cancer and may also act as a tumor suppressor protein. Previous research has shown that the expression of MSMB declines progressively as prostate cancer advances from early to late stages.

In the new study, the team investigated how the SNP may be related to MSMB function and the development of prostate cancer. They first verified that the SNP is associated with prostate cancer risk. To do so, they compared a region of chromosome 10 that included the SNP and MSMB in blood samples collected from 6,118 men with prostate cancer and 6,105 men without prostate cancer from NCIís Cancer Genetic Markers of Susceptibility (CGEMS) project. This analysis confirmed the strong association of the SNP with prostate cancer.

The team next examined how the two identified variants, or alleles, of the SNP affected the expression of MSMB. The SNP is found as either a C allele or a T allele. This means that some people may have a thymine (T) base at that place in their DNA, whereas other people have a cytosine (C) at that location.

The researchers found that the T allele (the allele that was more common in prostate cancer patients) was associated with lower expression of MSMB than the C allele. Further analyses showed that the transcription factor CREB — a protein that plays a role in turning on gene expression — binds strongly to the C allele but does not bind to the T allele, which lacks a CREB binding site. The team also found that no other SNP within the MSMB region seemed to play a role in the expression of the gene.

"There is mounting evidence that the T allele is associated with prostate cancer risk and decreased expression of MSMB," said study author Meredith Yeager, Ph.D., of NCIís Division of Cancer Epidemiology and Genetics. "The difference observed between the C and T alleles explains the majority of the change in prostate cancer risk observed in the genome-wide association study. However, more work is necessary to say that the T allele is directly causing prostate cancer and to determine if other genetic variations also contribute to this risk."

"This important finding about biological function associated with prostate cancer risk demonstrates the power of genome-wide association studies to provide new and unexpected insights into the genetic underpinnings of cancer etiology," said Joseph F. Fraumeni, Jr., M.D., director of the Division of Cancer Epidemiology and Genetics.

Prostate cancer is the most common cancer in men, excluding skin cancer, and the second leading cause of cancer-related death in men in the United States. African American men have the highest risk of developing this disease compared with men of other racial and ethnic groups. Most of the CGEMS genome-wide association study data are from white men. The Yeager team is currently working with other researchers to evaluate whether the SNP is also associated with prostate cancer among other ethnic groups.

In addition to Yeager, the study was led by Stephen Chanock, M.D., also of DCEG and Michael Dean, Ph.D., and Hong Lou, Ph.D., of NCIís Center for Cancer Research.

For more information on NCI's Cancer Genetic Markers of Susceptibility (CGEMS) initiative, please visit http://cgems.cancer.gov.

NCI leads the National Cancer Program and the NIH effort to dramatically reduce the burden of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI Web site at http://www.cancer.gov or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
Reference: Lou H., Yeager Y, Li H, Bosquet JG, et al. Fine mapping and functional analysis of a common variant in MSMB on chromosome 10q11.2 associated with prostate cancer susceptibility. Proceedings of the National Academy of Sciences. Online April 20, 2009.

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