Study Provides Clues About How a Common Genetic Variant May Increase Prostate Cancer Risk

The Bottom Line

Researchers have discovered that a common genetic variant previously associated with an increased risk of prostate cancer reduces the expression of a gene called MSMB in prostate tissue. This finding is consistent with other research suggesting that MSMB plays a role in prostate cancer development.

The Whole Story

Prostate cancer is the most common cancer diagnosed among men in the United States besides nonmelanoma skin cancer, and it is the second leading cause of cancer death among U.S. males. Several risk factors have been identified for prostate cancer, including age, race, and a family history of the disease. Researchers hope that learning more about the hereditary factors that contribute to prostate cancer development will result in better screening tests and earlier detection, as well as new treatments for the disease. Regions of the human genome associated with prostate cancer risk have been previously identified, but little is known about how these regions influence risk.

Recently, results from two independent genome-wide association studies showed that a common genetic variant, known as a single-nucleotide polymorphism (SNP), on human chromosome 10 is associated with an increased risk of prostate cancer. This SNP is located near the start point of the MSMB gene, which produces a protein called prostatic secretory protein 94 (PSP94), or beta-microseminoprotein. PSP94 is a small protein that is made by the prostate gland and is abundant in seminal fluid. Other studies have shown that MSMB gene expression declines progressively during prostate tumor progression, and a loss of MSMB expression is associated with prostate cancer recurrence. Although the biological function of PSP94 is not known, some evidence suggests that it may act as a tumor suppressor protein (a protein that helps limit cell growth).

The physical location of the prostate cancer-associated SNP suggested to researchers that it might affect MSMB gene expression. To investigate this possibility, a team of scientists, including some at the National Cancer Institute, examined whether the normal (more common) DNA sequence and the variant DNA sequence at the site of the SNP were associated with differences in MSMB gene expression. In the variant sequence, the DNA base thymine (T) replaces the normal base cytosine (C).

Laboratory experiments with prostate cancer cells and other types of cells revealed that the variant DNA sequence was associated with reduced expression of the MSMB gene. Expression was lowest in cells that had two copies of the variant sequence (one inherited from each parent). Other experiments showed that the transcription factor CREB (cyclic AMP response element binding) binds strongly to the SNP site when the normal DNA sequence is present but doesn’t bind at all when the variant sequence is present. Transcription factors are proteins that help turn on gene expression.

Although many SNPs have been associated with a variety of diseases, for only a few of these SNPs has a mechanism for the disease association been identified. By demonstrating that a prostate cancer-associated SNP alters the expression of a gene that had already been implicated in prostate cancer, the researchers have obtained independent evidence that this gene is likely involved in the development or progression of the disease. In future studies, the researchers will try to identify other DNA variants that may also affect MSMB gene expression. In addition, the precise relationship between MSMB/PSP94 expression and prostate cancer risk remains to be determined.

Reference: Lou H, Yeager M, Li H, et al. Fine mapping and functional analysis of a common variant in MSMB on chromosome 10q11.2 associated with prostate cancer susceptibility. Proc Natl Acad Sci 2009; 106(19): 7933-7938.