NEWS

Consortia, ‘Big Science’ Part of a Paradigm Shift for Genetic Epidemiology

Karen Kreeger

The field of cancer genetics and epidemiology is experiencing a revolutionary shift in approach. Researchers are looking at gene–environment relationships in cancer on a larger scale with new technologies and with more laboratories collaborating than ever before.

Investigators have long pondered how to best analyze low penetrance susceptibility genes, and in particular how to look at them in conjunction with a host of nongenetic factors from lifestyle choices such as cigarette smoking to external exposures, said Robert Hoover, M.D., director of the Epidemiology and Biostatistics Program at the National Cancer Institute.

"We’re about there technologically, and we’re going to see very shortly massive undertakings where investigators will be able to look at multiple genes, maybe three or four variants per gene, and in combination with each other and with exposure," predicted Hoover. "The promise of the revolution in molecular science and genomic technology for large-scale epidemiology studies is now here." In March, Hoover chaired a session at the American Society of Preventive Oncology annual meeting entitled, "Genetic Epidemiology: A Paradigm Shift to Big Science."

In the mid-1990s, then NCI director Richard Klausner’s Cancer Genetics Working Group—charged with bringing molecular genetics to cancer research—steered the way the institute marshaled resources for cancer epidemiology. The group made recommendations in the area of high penetrance genes involved in familial cancers, for example, coming up with mechanisms to facilitate studies of large groups of high-risk families, including those with BRCA mutations. They also gave advice about how to study the impact of susceptibility, low penetrance genes in the general population.

The working group recommended that such research move toward being done by consortia, an approach that differs considerably from what is generally still done. "Each investigator at each institution studies the genetics of one type of cancer and does so in a relatively small sample size," said Hoover. Once those results are published, other investigators try to replicate it.

"However, along with the molecular and genomic opportunities come complexities," Hoover said. For complicated studies that look at gene–environment interactions in cancer, consortia may be the best way of proceeding, primarily because of the large sample sizes needed and the need for rapid tests of initial findings. "If you’re looking at multiple genes, say three genes that operate on the same pathway plus an environmental exposure, the number of comparisons is going to give you many false positives," said Hoover. "When we scale these studies up to more complicated multiples of genes and exposures, the fear is that, if we do it in the way we’ve done in the past, we’ll waste a lot of investigator time and money chasing down false positives. It distracts people from pursuing the real associations."

Consortia are a way to maximize the opportunity to only pursue good leads. For example, several institutions, including Harvard University, the American Cancer Society, the University of Southern California, and the International Agency for Research on Cancer, which have been following cohorts of participants—some for decades—and have amassed tens of thousands of blood samples and health data on individuals, are collaborating with such international genomic institutions as Whitehead Institute in Cambridge, Mass., NCI, Centre d’Etude du Polymorphisme Humain (CEPH) in France, and Cambridge University in the United Kingdom in a cohort consortium study on breast and prostate cancer.

Last September, Immaculata De Vivo, Ph.D., assistant professor of medicine at the Harvard Medical School and assistant professor of epidemiology at the Harvard School of Public Health, Boston, and colleagues published one of the few studies that related a relatively common polymorphism to a common disease in women, endometrial cancer.

Using mouse knockout studies, gene sequence databanks, and molecular epidemiology, they found that a variation in the promoter region of the human progesterone receptor gene upsets the balance of two forms of the progesterone receptor protein. Women who had the variant were more likely to contract endometrial cancer than those without it. Having more of one form of protein over the other caused estrogen-induced proliferation of endometrial cells.

The researchers also found that the susceptibility gene—when present in conjunction with obesity—increased the patient’s likelihood of having endometrial cancer.

To study susceptibility, investigators need to know the variations that exist within a gene. It will be these variations that are more subtle in terms of an effect. But because a substantial number of De Vivo’s sample group had the variant—15% of the endometrial cancer cases and 11% in the matched controls—this common variant has more of an impact on a population level than other polymorphisms.

De Vivo took advantage of the large database from the Nurse’s Health Study, part of the cohort consortium study, which helped achieve the large sample numbers needed for her genetic epidemiology study.

"The shift to big science in my mind is going from traditional epidemiology, where it’s mostly observational studies, to a marriage with molecular biology and taking advantage of tools like the genome project, which gave rise to the polymorphism databases [that] we now use in association studies," said De Vivo.

In general, it is difficult to find susceptibility genes in humans, noted Peter Demant, M.D., Ph.D., of Roswell Park Cancer Institute, Buffalo, N.Y. "The reason is a statistical problem. When we look for the gene at 30,000 places in the genome, the chance that something will show up is just random. The genome is so large you have to look at so many places, so the chance that you find something [that] is real is minimal."



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Dr. Peter Demant

 
Demant and colleagues use mice to narrow down where susceptibility genes lie in humans so investigators only have to look at a limited number of places. This strategy is based on a paradox of cancer genetics: the relative impact of strong versus weak genes. So-called strong genes found in such cancers as familial adenomatous polyposis, in which "everyone that has the gene gets the disease," have a small impact on total cancer deaths. In contrast, so-called weak susceptibility or modifier genes, which are numerous and a person carrying such genes has a 10% to 20% higher chance of developing cancer, have a large impact on cancer deaths. And most weak genes work in concert with related genes and environmental triggers.

For example, Demant’s group has found 30 weak genes for lung cancer and their approximate location in mice. "Now we need to narrow that down" for humans, he said. His group is also working with colon cancer, lymphomas, and mammary tumors.

"We’re now on the cusp of being able to try these new approaches," concluded NCI’s Hoover. "People can agree to look at the same factors in the same way and use the same assays, and they’ve agreed to analyze data simultaneously so they’ll know what everyone else is finding. At the end, we may have a set of really good candidates for gene–environment or gene–gene–environment interaction that the next generation of studies can look at more biologically without sending people down false paths."



             
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