Common Variations In Gene Segments That Increase The Risk For Prostate Cancer

"Discovery of common variations is very exciting. Building on this finding we may be able to identify men at highest risk for prostate cancer, diagnose the disease earlier, and hopefully prevent it all together. One of the next steps is to understand the mechanism by which genetic variation exerts its effect on cancer risk," said NCI Director John E. Niederhuber, M.D.

The latest gene variations were discovered on chromosomes 7, 10 and 11 while the initial variation was discovered on chromosome 8. Humans normally have 46 chromosomes in each cell, divided into 23 pairs. For example, two copies of chromosome 8, one inherited from each parent, form one of the pairs. Chromosome 8 spans about 146 million base pairs (the chemicals that comprise DNA), represents about 5 percent of the total DNA in cells, and contains an estimated 700 to 1,100 genes.

In the February 2008 report, researchers confirmed and extended findings on chromosome 8 and other regions as well as provided strong evidence for four novel associations and suggestive associations for an additional nine locations. On chromosome 10, one region corresponds to a gene that codes for a protein that is the primary component of semen and is a proposed biomarker for early detection of advanced prostate cancer. The region discovered on chromosome 7 contains a gene that may be related to endometrial cancer. On chromosome 11, researchers found a region of significance in a gene-poor region of the DNA, resembling the finding from May 2007 on chromosome 8.

The proportion of all prostate cancer that could be explained by these gene variants, individually and combined, is substantial. The increased risk conferred by these loci was observed for all age groups studied.

"CGEMS allows us to look systematically across the entire human genome and search for common genetic variations that confer risk for prostate cancer, a very common and very complex disease" said Stephen Chanock, M.D., director of NCI's Core Genotyping Facility.

"Identification of new regions furthers efforts to uncover the genetic basis of prostate cancer, which may eventually lead to more insights into cancer causation in general," added Gilles Thomas, M.D., Ph.D., of NCI. In addition to Chanock and Thomas, CGEMS is co-led by Robert Hoover, M.D., Sc.D., also of NCI, and David Hunter, M.D., Sc.D., from the Harvard School of Public Health, Boston, Mass.

An initial genome-wide association study was conducted in 2,329 men from across the United States. These men are participating in the NCI's Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) that began in 1993. The PLCO analysis compared 1,172 men with prostate cancer to 1,157 who did not have cancer.

The initial results were further confirmed by a coordinated effort of the NCI Cohort Consortium, including collaborating investigators from the American Cancer Society Cancer Prevention Study II, the Health Professionals Follow-up Study at Harvard and the NCI Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study as well as the CeRePP French Prostate Case-Control Study. Combined, these studies enrolled 6,266 men.

Prostate cancer is the third-leading cause of cancer-related death in men yet very little is known about its origins. In 2007, there were an estimated 219,000 new prostate cancer cases and an estimated 27,000 deaths in the U.S.

The CGEMS database will soon contain close to 2.5 billion genotypes, allowing researchers to identify genetic risk factors for breast and prostate cancers using 540,000 snippets of DNA. By comprehensively surveying for common genetic variations and following-up promising findings in confirmatory studies, researchers hope to identify and verify associations that increase or decrease the risk of these cancers.

Analyses and data from the CGEMS study will be available through NCI's caBIG™ (Cancer Biomedical Informatics Grid™), at http://caIntegrator.nci.nih.gov/cgems/. The summary results from the scan in PLCO and similar data on breast cancer are already freely available to other researchers at this Web site.

Journal reference: Thomas G, Jacobs KB, Yeager J, et al. Multiple novel loci identified in a genome-wide association study of prostate cancer. Nature Genetics. Online February 10, 2008. In print March 1, 2008.

Earlier article: Yeager M, Orr N, Hayes RB, et al. Genome-wide association study of prostate cancer identifies a second locus at 8q24. Nature Genetics. May 1, 2007.