Scientists identify major genetic risk factor for prostate cancer
A tissue sample from a prostate tumor
Image courtesy of Otis Brawley, National Cancer Institute
Prostate cancer is one of the most common cancers in men in the United States. It is particularly prevalent among African American men, in whom the disease is not only more frequent, but often more deadly. Although the genetic picture of this disease has been far from crystal clear, a team of scientists led by David Reich, an assistant professor at Harvard Medical School and a Broad associate member, has used a new genetic mapping technique known as "admixture mapping" to identify a strong genetic link to prostate cancer, especially in African American men. The findings, which appear in the August 21 advance online edition of the Proceedings of the National Academy of Sciences, confirm a previously reported genetic association to prostate cancer and help to focus future research efforts to a defined "genetic neighborhood" — one that likely contains a major, and as yet unidentified, prostate cancer risk gene.
Admixture mapping can be a particularly efficient and powerful method for dissecting the genetic underpinnings of complex diseases, which, like prostate cancer, often vary in frequency among different populations. The technique was first conceived more than 50 years ago, but has only recently been possible due to scientific advances in detecting and analyzing human genetic variation on a comprehensive, genome-wide scale. It involves systematically searching the genome for small genetic differences in individuals who have a particular disease and originally descended from two or more distinct geographic regions — such as African Americans, whose ancestry lies in both West Africa and Europe, or Hispanic Americans, whose ancestry lies in the Americas and Europe. Such genetic variants are present across all human populations, but their precise distribution can provide clues about the genetic factors that underlie common and genetically complex diseases.
Reich and his colleagues began by analyzing nearly 2,500 DNA samples from two groups of African American men, a "disease" group with a history of prostate cancer and a "control" group of healthy individuals. The study's co-first authors include Matt Freedman, a cancer geneticist at the Dana-Farber Cancer Institute and at the Broad Institute; Nick Patterson, a senior research scientist and statistician at the Broad; and Christopher Haiman, a researcher at the University of Southern California. The researchers conducted a whole-genome "admixture" scan, looking for specific genetic regions that are common among the men with prostate cancer and have an unusually strong geographic contribution from West Africa compared to Europe. Because prostate cancer is known to be more prevalent in Americans who have African ancestry, an uncharacteristically high genetic input from African regions could point to an underlying genetic risk factor for the disease.
This analysis revealed a region on chromosome 8 that is significantly associated with prostate cancer, particularly in African American men. The risk locus is about 4 million base pairs in length and nearly doubles the prostate cancer risk to African American men who are under age 72. Strikingly, this genetic risk profile parallels the known epidemiological risk for the disease, which is higher in younger African American men and subsides with age. Moreover, it is predicted that about 49% of all prostate cancer cases in African American men under the age of 72 result from inheriting this genetic region.
The same chromosomal region was previously implicated in prostate cancer by a team of researchers from deCODE Genetics who used a different genetic mapping strategy to pinpoint two specific genetic variants associated with the disease. The researchers in the current study replicated these earlier findings, but found that they accounted for only a small fraction of the genetic risk that the chromosome 8 region carries, which means that other significant risk factors within the region remain to be defined. Other Broad scientists involved in this work include David Altshuler, Kristin Ardlie, Gavin McDonald, Kathryn Penney, Arti Tandon, Alicja Waliszewska, as well as researchers from Harvard Medical School, Brigham and Women’s Hospital, Massachusetts General Hospital, University of Southern California, Stanford University and University of Michigan.
The prostate cancer risk locus highlighted in this study contains a total of 9 genes and represents about one-thousandth of the human genome. While it carves out a substantial patch of genetic ground to be covered in the search for the gene (or genes) responsible, the work is notable for unearthing one of the first common genetic risk factors for cancer. Indeed, specific inherited risk factors for other forms of cancer have been identified — in breast cancer and in colon cancer, for example — yet, unlike the prostate cancer risk locus on chromosome 8, they tend to be rare in the overall population and account for a relatively small proportion of their respective cancers.