Dr. Stephen Thibodeau from the Mayo Clinic talks about hereditary prostate cancer.
What about the association between BRCA2 and prostate cancer?
There are some families that have BRCA2 mutations in prostate cancer. BRCA2 is one of the genes that has been identified in familial prostate cancer. But BRCA2 accounts for a very small percentage of prostate cancer cases, unlike what you might see in hereditary breast cancer. Some of the mismatch repair genes have also been shown to be involved in prostate cancer, but these also occur in a small fraction of the cases. There are really generally two types of genetic studies that have been done for prostate cancer. One is to look for these major genes, those genes that have high penetrance—that is, if you find a mutation in these genes, there is a high likelihood that the man will develop disease. An example of this is BRCA1 and BRCA2 for breast cancer or APC for colon cancer. As previously mentioned, finding these types of genes for prostate cancer has been very challenging.
What is the other type of study being done?
The other type of genetic study being done is called a genome-wide association study (or GWAS). These studies take advantage of the fact that there are a large number of common variants within individuals and within the population. This type of study, then, looks at these common changes in DNA in the population, or common polymorphisms, and tests whether or not some of the changes are found more frequently among affected men compared to normal men. Among the million common DNA changes known to be present in the population, about 100 of these have now been found to be associated with prostate cancer. Unlike highly penetrant genes, like BRCA1 and 2, these common variants increase the risk for prostate cancer by only a very tiny amount. This type of genetic study has actually been very productive for prostate cancer compared to other malignancies.
Very large studies have now been done. Some groups have looked at 40,000 cases with prostate and 40,000 controls, looking for differences in DNA among the cases compared to the controls. As I mentioned, over 100 DNA variants now have been identified, with each variant individually increasing prostate cancer risk. If you look at individuals who might have multiple variants present, then the risk increases even more. The data so far suggests that these risk variants may account for about 30% of what we expect the hereditary component of prostate cancer to be. If you have these variants, your risk increases, but it’s a very small risk in comparison to the general population.
Broadly speaking, those are the two main types of ongoing studies, with the idea that there is still a genetic component that it is not completely understood.
Is it a matter of looking more in-depth at the samples and the data that you already have, or is it that as the pace of technological innovation accelerates, we’ll learn more? (It’s only been a short time since we’ve developed the capability to quickly sequence the entire genome…)
Dr. Thibodeau: I think it’s a little bit of both. We’re really taking advantage of the sequencing capability that we haven’t had in the past. A lot of the methods that we’d used in the past to identify the genes were really indirect. BRCA1 and BRCA2 and the mismatch repair genes were all identified by a technique called linkage analysis, which is a way to globally look at all genes. Indirectly, you take a family and you look at markers scattered across the genome. You’re looking to answer the question, “Do these markers follow disease in the family?” If they do follow disease in the family, then you look for genes around that marker. It doesn’t really tell you what the gene is; it just tells you a location on the chromosome.
It is really only within the past five years with the introduction of next-generation sequencing capability that we can now sequence every gene. Rather than searching for genes indirectly, which is really very difficult to do, we can now look at genes directly. The idea is that we’ll take every gene and sequence them for all of the individuals in the family and then look for differences. What are the differences in each gene in men with prostate cancer compared to what we might see in men who don’t have prostate cancer. If you sequence enough individuals, you can begin to appreciate what is different in the groups that have cancer compared to the groups that don’t.
This is really the first time we’ve been able to use this technology. That is why we’re more hopeful. As newer technologies emerge, we have a better chance of identifying what might be present in familial prostate cancer. The technology is definitely having an impact and increases our chances.
The other important issue is that the biology of prostate cancer is very difficult. The disease is complex. Since prostate cancer is so common, it might be that some of the prostate cancers that we see in our families are not due to genetic causes; they’re due to something else.
What do you mean?
Like many diseases, there can be multiple causes. First, there are a variety of environmental factors that increase risk. Second, it is often the case that the disease is not caused be a single gene. There are often several genes that come into play. Finally, all of these factors play a role, so in the end you have multiple genes and then all of the environmental factors that come together to result in a disease process. All of these factors are still being sorted out for prostate cancer.
You may have a mixture within a family: some individuals have prostate cancer due to a genetic cause and some have prostate cancer due to another cause. The technology allows us to look at things that we weren’t able to look at before, but the biology is still very difficult and that complicates our ability to identify these genes. We’re still optimistic that over time we’ll identify more genes.
How does all of this play out once you’ve identified a gene? There are some companies that offer BRCA2 testing. How useful to patients are those commercial tests?
They’re very useful for the disease they target. For BRCA1 and BRCA2, clinicians now routinely test women at risk for breast and/ or ovarian cancer. The tests are a very important part of the toolkit that physicians have for at-risk individuals. (At-risk individuals are typically individuals who are very young when they develop a disease, or who have a family history.)
For some of these cancers— for colon, breast, and prostate, for example—one can do prophylactic, or preventative, surgery. Importantly, if you identify high-risk individuals, then these individuals can be monitored more carefully and more frequently with the goal of early detection and early treatment
To read Dr. Stephen Thiodeau’s interview, fill out the form here to get a free copy of our June 2016 issue.