| New Findings Published from PROGRESS Our last newsletter reported on the completed genome scan of PROGRESS families. (A genome scan is a technique used to find disease genes by looking for patterns of inheritance at many different markers, or “stop signs,” along the genome; this allows us to see whether or not individuals with prostate cancer share the same marker patterns.) Our results highlighted several areas of the genome that could harbor hereditary prostate cancer genes. Published in the same journal issue were seven other hereditary prostate cancer genome scan papers from research groups around the world. Each of the eight scans highlighted different regions of the genome, with very few overlapping results. This is strong evidence that there are likely to be several genes that cause prostate cancer to occur in families. The latest research report published from PROGRESS focuses on a single region on chromosome 7 that was associated with prostate cancer in our genomic scan overall, and in particular in a subset of families.
We identified our strongest finding on chromosome 7 by looking at a subgroup of the PROGRESS families reporting Jewish heritage. This approach of looking at groups of similar families has proven to be very helpful in locating other disease genes, like the genes for inherited breast cancer (called BRCA1 and BRCA2). The families who enrolled in PROGRESS are from different backgrounds and from all across North America. Because the families are so different (i.e., heterogeneous), it’s possible that there is more than one gene responsible for prostate cancer in these families. By sorting families into groups with similar characteristics (i.e., homogeneous), we hope to increase our ability to find the disease genes. Finding a gene using linkage analysis is a little like tuning in a radio station – once we decrease the noise or static the signal gets stronger. Thus, by focusing on a more similar or homogeneous subset of families we may be able to reduce the noise and thereby pick-up important signals highlighting the location of potential prostate cancer genes. We have analyzed other subgroups of PROGRESS families in the past, most notably according to the presence of other cancers within a family. Such an approach helped to find our linkage result on chromosome 1p in families with both prostate cancer and brain cancer.
For our latest result on chromosome 7 we looked at a subset of families who reported their religion or ethnicity as Jewish and who reported that their parents or grandparents came from Central or Eastern Europe. We decided to focus on this subgroup because there is a specific and well-studied population of Jewish people called “Ashkenazi” whose ancestors lived in Europe many years ago. Because of their genetic isolation in the past, due to geography and marriage patterns, Ashkenazi Jewish families may have a more similar genetic profile to each other than would an unselected (more heterogeneous) group of families. We do not know for sure which families in PROGRESS are descended from the Ashkenazi Jewish population, but we tried to identify families likely to be Ashkenazi based on reported religion, ethnicity, and country of origin. After applying these criteria, a small group of 17 families remained.
With such a small number of Jewish families, it could be difficult to get a strong result. To improve our ability to detect a genetic signal, we worked with researchers at the Johns Hopkins University (JHU) in Baltimore, MD who have been conducting a family study of prostate cancer similar to PROGRESS and had identified a small group of 19 Ashkenazi Jewish families. By combining our efforts, we were able to increase the number of families we could study and had more power to detect an association. Together, there are 36 families in the PROGRESS and JHU collections who reported Jewish ancestry and originated from Central or Eastern Europe.
With the combined data on these 36 families, we re-analyzed the genome scan data. We use a technique called “linkage analysis” to determine whether a DNA marker and the disease (prostate cancer) are inherited together more frequently than would be expected by chance alone. The genome scan analysis highlighted a region on chromosome 7. We found eleven sequential genetic markers with positive signals, indicating this part of the chromosome could harbor an inherited mutation in a gene. If we repeated the experiment 1,000 times, we would expect to get a result this strong only six times by chance, a statistic called a p-value.
The importance of this result is not limited to Jewish families, even though that is the group where we first found a signal. Looking in Jewish families may help to “tune in” a weak signal, but the gene identified could be relevant for non-Jewish families. We know this from the research already conducted in breast cancer. The breast cancer gene BRCA2 was initially identified by a linkage signal found in a subset of families with both male and female breast cancer. (Yes, males can get breast cancer, though it is rare.) By looking in this rare subgroup, the genetic signal for hereditary breast cancer became stronger and a gene with mutations that cause breast cancer was later identified in that area of the genome. Once the BRCA2 gene was identified, mutations in that gene were found to account for breast cancer cases in many families without cases of male breast cancer. Based on that experience, we know that our prostate cancer result in Jewish families could be very important for non-Jewish families too.
The next step in this process of gene discovery is to narrow down the region we have identified and ultimately to find the specific gene responsible for the disease. Within the area we have identified, there are up to two hundred genes depending on how the region is defined. The lab scientists here at the Fred Hutchinson are working very hard to pinpoint which of those genes could harbor a disease-causing mutation(s). We are also working with other researchers in the ICPCG (International Consortium for Prostate Cancer Genetics) to analyze additional Jewish families with prostate cancer. The more families we have, the more genetic information we will gain to help narrow the region and pinpoint the gene. We are hopeful that with further work, we will be successful in our search. As always, we will keep you updated as our research develops.
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