April 11, 2013 — In the largest-ever study of its kind, an international collaboration of hundreds of scientists has uncovered 74 new genetic markers linked to three common hormonal cancers—breast, prostate, and ovarian—thus setting the stage for new treatments, targeted screening, and a greater understanding of how these diseases develop.
The findings were outlined in a series of 13 research papers in five different journals. Harvard School of Public Health (HSPH) researchers contributed to five of the papers, which were published March 27, 2013 in Nature Genetics. The other studies were published in Nature Communications, PLoS Genetics, Human Molecular Genetics, and the American Journal of Human Genetics.
“These papers are significant because they have greatly increased our knowledge of the genetics underlying breast, prostate and ovarian cancer,” said Peter Kraft, HSPH professor of epidemiology and senior author of a paper that uncovered four new variants linked with an aggressive form of breast cancer called estrogen receptor (ER)-negative. “These findings will generate biological hypotheses that could lead to potential treatments down the road. In addition, we’ve now learned enough about these variants to start thinking about using them in the clinic—for instance, we could potentially identify women who might benefit from earlier breast cancer screening.”
The discovery of the 74 new genetic variants nearly doubles the number previously known for the three hormonal cancers, which strike roughly half a million Americans each year and affect 2.5 million people globally, killing about a third. Finding these additional small genetic alterations is significant because while a single alteration—known as a single nucleotide polymorphism, or SNP—raises cancer risk only slightly, a person with many SNPs faces higher risk. Clinicians could potentially use this new information to help guide their patients’ care.
The power of pooled resources
Scientists found the new variants by surveying genomic data from more than 200,000 people, half with cancer and half without cancer, and noting which variants are more common in people with disease. Participants were drawn from existing research cohorts, including several that HSPH researchers are involved in such as Nurses’ Health Study I and II, Physicians’ Health Study I, and Health Professionals Follow-up Study. The research was coordinated through a large international collaboration of 160 research groups known as COGS—the Collaborative Oncological Gene-environment Study.
The findings on ER-negative breast cancer—which represents 20%−30% of all breast cancers and occurs most frequently among younger women and women of African ancestry—confirms what researchers had already suspected: that ER-negative and ER-positive cancers are different diseases biologically. “This has significant implications for risk prediction, prevention, and treatment,” said Kraft.
Hunt continues for genetic clues to disease
Given the new findings, researchers are now able to attribute a greater percentage of these hormonal cancers to genetic risk factors. They estimate that genetic risk factors account for roughly 30% of the risk of breast and prostate cancer, and for about 4% of the risk of ovarian cancer. Other potential genetic risk factors remain unknown. However, scientists believe that larger genotyping studies could uncover further clues.
One notable finding about the breast cancer discoveries, Kraft said, “is the suggestion that this is just the tip of the iceberg—that, in fact, there may be as many as 1,000 other variants out there yet to be discovered, somewhere in the genome.” Several international cancer research consortia have already joined to launch a follow-up study—using a much larger sample size—aimed at finding additional variants. Kraft and others at HSPH, including David Hunter, Vincent L. Gregory Professor in Cancer Prevention and Dean of Academic Affairs, are helping lead this effort as part of GAME-ON, a National Cancer Institute-sponsored initiative to better understand the biology and public health implications of genetic associations with multiple cancers.
Other HSPH researchers involved in the five Nature Genetics papers include Hunter as well as a number of researchers from the Department of Epidemiology: Constance Chen, programmer/analyst; Daniel Cramer, professor; Sara Lindstrom, research associate; Lisa Signorello, associate professor of epidemiology (who participated while working at Vanderbilt University); Kathryn Terry, assistant professor; Dimitrios Trichopoulos, Vincent L. Gregory Professor of Cancer Prevention; and Shelly Tworoger, associate professor.
photo: Aubrey LaMedica