Admixture mapping reveals locus for prostate cancer risk
Aug 22, 2006 - 4:23:37 AM
Harvard Medical School researchers have identified a DNA segment on chromosome 8 that is a major risk factor for prostate cancer, especially in African American men. The paper appears in the August 21 electronic edition of the Proceedings of the National Academy of Sciences (also see PNAS's news tip below).
"This paper identifies a genetic risk factor that about doubles the likelihood of prostate cancer in younger African American men," says principal investigator David Reich, PhD, Harvard Medical School assistant professor of genetics with the HMS Department of Genetics and the Broad Institute. "This finding may explain why younger African Americans have an increased risk for prostate cancer than do other populations--and may also explain why this increased risk in African Americans attenuates with older age."
"This is one of the first genetic risk factors found that is responsible for an appreciable fraction of sporadic prostate cancer cases, particularly for the African American population," says lead author Matthew Freedman, Harvard Medical School instructor of medicine at the Dana-Farber Cancer Institute and the Broad Institute "Interestingly, we found that this region also confers risk for prostate cancer for diverse ethnic groups. The actual gene, however, remains to be identified."
The researchers used their newly developed method of "admixture mapping" to screen through the genome in African Americans (who have both African and European ancestry), searching for the segments where individuals with disease have more of one ancestry than the average. The key epidemiological fact is that prostate cancer occurs approximately 1.6-fold times more often in African Americans than in other populations. This prompted the hypothesis that there is a genetic risk factor for prostate cancer that occurs at higher frequency in African than in other populations, and that can be found by searching for a region where the proportion of African ancestry is higher than the genome average.
Reich, Freedman and their colleagues studied 1,597 African Americans with prostate cancer. They found a section of the genome in the patients that had much more than the average proportion of African ancestry, rising from 78 percent to about 85 percent. The risk factor is localized to a tiny fraction (about a thousandth) of the genome, a section on chromosome 8 containing just 9 genes.
A particularly exciting aspect of this work is that in May a separate research team also identified a genetic variant occurring within the same region, which increases risk for prostate cancer. The study by Reich and colleagues makes two additional advances. One important result is that the genetic risk factor is more important for individuals with younger age. Second, they show that the specific genetic variant reported in the earlier paper can explain only at most a small fraction of the increased risk to African Americans. Thus, major unidentified risk factors remain to be found.
A whole genome analysis has revealed a section on chromosome 8 as significantly associated with African-American's increased risk to prostate cancer. African Americans have about a 1.6 higher risk of developing prostate cancer than European Americans; at least part of this difference is likely a result of genetic factors. Taking advantage of recent advances, David Reich and colleagues used admixture mapping to try and find these factors. The concept of admixture mapping is to scan the genes of mixed ancestry populations (such as African Americans, descended from Africans and Europeans over the last 15 generations), searching for regions where the proportion of DNA inherited from one side is unusual. The authors found that a 3.8 million base region of chromosome 8, termed 8q24, substantially increased prostate cancer risk in men who inherited the African ancestry. Interestingly, this increase was greater in men diagnosed before the age of 72, correlating with observations that prostate cancer risk in African Americans attenuates with age. This same region, which contains 9 known genes, was recently identified by linkage analysis. However, the authors found their results cannot be explained by the two genes proposed in the other analysis; therefore, the major risk gene(s) for prostate cancer remain unidentified.
Admixture mapping entails scanning the genes of mixed ancestry populations to find regions where the proportion of DNA inherited from either ancestral side is unusual compared to the genome-wide average. This technique could be useful in uncovering risk variants, although it has only recently become practical. Matthew Freedman et al. have now applied admixture mapping to find genes for prostate cancer, taking advantage of its markedly increased incidence rates in African American men. Their analysis of 1,597 cancer cases and 873 controls revealed a 3.8 Mb section of chromosome 8, termed 8q24, that contributes to an increased cancer risk in African Americans with African (as opposed to European) ancestry at this region. There is also a highly significant association between risk and age at 8q24, which correlates with epidemiology studies that show that the elevated incidence of prostate cancer in African Americans compared with other populations attenuates with age. A recent linkage analysis also highlighted a risk association in this region, but Freedman et al. report that the previously described alleles only explain a fraction of the admixture signal; therefore 8q24 still contains a major unidentified risk gene for prostate cancer.
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