Gene-Environment Interactions Major Research Challenge

ABSTRACT: Every 3 years, the National Cancer Institute (NCI) asks cancer researchers, advisory groups, and advocacy organizations to recommend important areas to which it should devote additional resources. NCI defines such "extraordinary opportunities for investment" as "broad-based, overarching areas of scientific pursuit that hold tremendous promise for significantly expanding our understanding of cancer."This is the first in a series of interviews exploring the progress and promise of NCI’s six current extraordinary opportunities: genes and the environment, cancer imaging, defining the signature of cancer cells, molecular targets of prevention and treatment, research on tobacco and tobacco-related cancers, and cancer communications.

BETHESDA, Maryland—Untangling the interactions between genes and the environment poses a major research challenge and a significant opportunity to improve cancer prevention and control. The potential for discovery includes how various environmental factors, including contaminants and life-style behaviors, affect genes; why some people are more susceptible to cancers than others; and new ways to assess an individual’s genetic risks for specific cancers.

The National Cancer Institute has named gene-environment interactions as an area in which intensifying research could pay enormous dividends. Robert A. Hiatt, MD, PhD, deputy director of NCI’s Division of Cancer Control and Population Studies, discussed the Institute’s efforts with Patrick Young, ONI’s Washington Bureau Chief.

Oncology News International: What has led to the integration of cancer genetics with the study of environmental risk factors?

Dr. Hiatt: Epidemiologists have focused on the environment for some time. They’ve looked at the effects of tobacco, diet, and pharmaceuticals, for instance, on cancer etiology. With the discoveries in genetics, the possibility has arisen of understanding how a gene might make someone more or less susceptible to these environmental factors.

So the interaction issue has become important in understanding whether different parts of the population may be more or less susceptible to environmental factors, which will be important in diagnosis, prevention, and follow-up.

ONI: What are the major environmental and life-style factors that you are focusing on at this time?

Dr. Hiatt: Tobacco is the biggest. Diet and hormones—supplements as well as endogenous hormones—are also important in many cancers. Environmental factors such as benzene, radiation, and radon are important. And other life-style factors, such as physical activities, are increasingly becoming a part of the cancer-causing picture.

ONI: Haven’t these had a lot of work devoted to them?

Dr. Hiatt: That’s true. They have been looked at, and we know they are all related to cancer. So we are starting from a large knowledge base, but we expect to expand that substantially.

Two new things are happening. First, the fact that some people are more susceptible to tobacco or other carcinogens than others may mean that there is a genetic basis for these effects. If so, what are the interactions that cause cancer? Second, by looking at genetic susceptibility, we may find cancer-causing agents or life-style factors that we weren’t aware of previously.

ONI: How well do we understand the interaction of specific genes with environmental forces?

Dr. Hiatt: Not very well. This is a new field, and it is fraught with pitfalls. In efforts to study these interactions, there have been a lot of unconfirmed findings. We think that part of this is because the size of studies needs to be substantially larger.

For instance, epidemiologists in the past have used case-control studies that involved maybe 200 or 300 cases. Now we believe we need something like 5,000 cases to look at the interactions we believe are important in order to come up with more definitive results.

ONI: What are NCI’s major goals in the gene-environment area?

Dr. Hiatt: Ultimately, we want to discover the genetic, environmental, and life-style factors and their interactions that define cancer risk to inform strategies for cancer control. We are looking for ways to apply what we have learned in cancer genetics to the clinical and the public health settings. We want this to help us in early detection, diagnosis, and treatment, which we expect would have an impact on the cancer burden.

These goals are related to a series of objectives that focus on a number of different infrastructures to make this happen. These include a cancer family registry, a mouse model consortium, and NCI’s Cancer Genetics Network.

These are all fairly large undertakings that only the NCI can do from a federal standpoint, and we believe they are important foundations on which to move forward.

ONI: In what ways will the mapping of the human genome help explain the gene-environment interaction?

Dr. Hiatt: Basically, it gives us a road map for where to look for important genes. In cancer, these are genes where the base pairs vary just a little bit between individuals. We need to identify these genes and their polymorphisms to move this ahead.

ONI: How is NCI fostering research in this area?

Dr. Hiatt: One way to think about this is to think about genes on the one hand and, on the other, about the environment. On the gene side, we are interested in supporting the discovery of genes, and one major way to do that is to study large families that are at higher risk of cancer. So we’ve supported cancer family registries.

On the environment side, we are trying to find better ways to characterize environmental exposure with less invasive measures such as buccal smears—inside of the cheek scrapings—instead of blood for DNA samples. We are also looking for ways to assess cumulative doses over a lifetime.

After gene discovery and better ways to characterize the environment, we need ways to study their interactions. To do that, we need these very large consortia. These large collaborations will allow this type of research to proceed.

Then, we need to find ways to apply the results. So we have established the Cancer Genetics Network, which is designed specifically to take what we have learned from cancer research and apply it to the medical practice setting. As the result of all this, we have a fairly logical funnel of activities that will bring this information to its relevant application.

ONI: Has any of this work led to clinical advances?

Dr. Hiatt: We are starting to learn about the risks of hormone replacement therapy in women who have mutations of the breast-cancer susceptibility genes BRCA1 and 2. This may be one of the first areas that will help us, but the field is still very young and we can’t point to a lot of successes as yet.

ONI: The National Institute of Environmental Health Sciences has a very active gene-environmental program (see "NIEHS Funds Six-Member Toxicogenomics Consortium"). How closely does NCI cooperate with NIEHS?

Dr. Hiatt: From my perspective, it could be better. Both NIEHS and the Centers for Disease Control and Prevention’s environmental laboratory are places where we could get a better handle on environmental exposures. Historically, it has been more their purview than the Cancer Institute’s to tackle this problem of the environment. But to get the best environmental measurements, I think collaboration is important.

ONI: How and when will this work change the way we do prevention, screening, diagnosis, and treatment?

Dr. Hiatt: That’s a good question, and the answers to it are not completely known. In the public health sense, most of the advice we give to people currently is one-size-fits-all—don’t smoke, eat five servings of fruits and vegetables a day, take drugs appropriately. It might be that when we understand genetic susceptibility better, we can tailor our advice for those who are truly at the highest risk.

Another way is that if we understand that genetic susceptibility exists and can test for it at appropriate times in life, then a woman who might be at increased risk of breast cancer could have more vigilant screening or undertake prevention measures, such as taking tamoxifen [Nolvadex]. And that is true for all cancers where we have effective screening.

Finally, there may be a genetic variation in how well people respond to cancer drugs. So with certain genetic factors in place, we might expect better or worse responses to therapy, and therapy could be tailored to the patient’s genetic characteristics.

ONI: What are some less obvious challenges ahead?

Dr. Hiatt: All of these activities are new, in the sense of how we do research. They will require a large-scale collaboration among population scientists that has not heretofore existed.

This raises a lot of questions, not the least of which are confidentiality of patient information from different datasets and intellectual property rights. People have worked decades to build up these large datasets. How do they benefit from them if they are going to be sharing data?

Another issue is that academic centers have always had young researchers who advance their careers by writing papers on which they are the first author. When you talk about larger-scale collaborations, new methods of recognizing contributions to science need to be worked out.

This area also may require new mechanisms to support research. The ones we have now work for single-investigator models but not for these large collaborations. And it may require a different view from the NIH or NCI standpoint about the importance of supporting existing population resources as resources and not just as hypothesis-driven projects.

A lot of the research that needs to be done represents a new paradigm. We at the NCI, as well as the extramural investigators we support, are struggling to find the best way to organize that work.