Researchers at the University of Pennsylvania School of Medicine have uncovered variation around two genes that are associated with an increased risk of testicular cancer.
Testicular cancer is the most common cancer among young men, and its incidence among non-Hispanic Caucasian men has doubled in the last 40 years -- it now affects seven out of 100,000 white men in the United States each year. The discovery, published in the May 31, 2009 online issue of Nature Genetics, is the first step toward understanding which men are at high risk of disease.
"Despite being quite heritable, there really have not been any clear genetic risk factor that can account for most cases of testicular cancer," says Katherine L. Nathanson, MD, an assistant professor of Medicine and a specialist in medical genetics at the Abramson Cancer Center. "These variants are the first striking genetic risk factors found for this disease to date."
Nathanson and co-author Peter A. Kanetsky, PhD, MPH, an assistant professor of Epidemiology, found that men who have two copies of the common version of the c-KIT ligand (KITLG) gene have a 4.5-fold higher risk of testicular cancer than men who have two copies of the less common or minor version of the gene. Additionally, men with two copies of the common version of variants next to another gene, sprouty 4 (SPRY4), have a 1.48-fold higher risk than men with two copies of the less common version of the gene.
While researchers suspect environmental exposures may play a part in the growing incidence, they now know that an individual's genes also play a major role in disease susceptibility.
"This finding is quite different than those observed in many other genome-wide association studies," Nathanson says. "In most studies, the increased risk of disease is associated with the less common variant of the gene. In this case, it is the more common variant in Caucasians that is associated with risk. If you carry two copies of the less common variant you are probably at incredibly low risk."
Additionally, the magnitude of the risk associated with the KITLG is much larger than has been found in similar studies of other adult cancers, including breast, colon, and prostate cancer. In those diseases, individual genes increase a person's risk by 10 to 25 percent, whereas the KITLG gene is associated with a 300 percent increase in risk for testicular cancer.
"Our observed strong association is intriguing and may reflect the impact of the genetic effect of KITLG," Kanetsky says. "However, since the prevalence of the common variant is so high, it may also reflect other underlying factors required in conjunction with KITLG for disease development. This remains to be determined."
Only a small proportion of men who carry the high-risk alleles will develop the disease. The key now, the researchers say, is to find out what modifies the genetic risks and pushes one individual toward cancer while another remains disease-free. By using the newly-discovered genetic risk factors as a lens, Nathanson and Kanetsky believe they may now be able to reveal critical environmental factors that would otherwise be lost in cloud of confounding information.
"We are very interested in how genes and environmental factors work together to increase one's risk," Nathanson says. "Now that we know something about the genetics, we hope to now build a better model of who is at risk by looking at gene-environment interactions."
Additionally, the new findings may begin to explain why white men are more often diagnosed with testicular cancer than African American men. KITLG is involved in pigmentation –– and the version of this gene associated with testicular cancer is common in the white population but much less common in the black population.
Finally, Nathanson says the findings show that previous models of testicular cancer formation are correct and underscore why men with testicular cancer may also have fertility problems. "Researchers have postulated testicular cancer was a disorder of germ cell development or maturation, and they were right," she says. "The KITLG gene is critical for germ cell development and maturation."
The study was funded by the University of Pennsylvania Abramson Cancer Center, Lance Armstrong Foundation, and grants from the National Institutes of Health.
In addition to Nathanson and Kanetsky, co-authors on the study included Nandita Mitra, Saran Vardhanabhuti, Mingyao Li, David J. Vaughn, Richard Letrero, Stephanie L. Ciosek, Lauren M. Smith, and Muredach P. Reilly of the University of Pennsylvania; David R. Doody, Chu Chen, Jacqueline R. Starr, and Stephen M. Schwartz of the Fred Hutchinson Cancer Research Center and the University of Washington in Seattle; JoEllen Weaver, Andrew K. Godwin, and Daniel J. Rader of the Fox Chase Cancer Center in Philadelphia, and; Anthony Albano and Hakon Hakonarson of The Children's Hospital of Philadelphia.
PENN Medicine is a $3.6 billion enterprise dedicated to the related missions of medical education, biomedical research, and excellence in patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.
Penn's School of Medicine is currently ranked #4 in the nation in U.S.News & World Report's survey of top research-oriented medical schools; and, according to most recent data from the National Institutes of Health, received over $379 million in NIH research funds in the 2006 fiscal year. Supporting 1,700 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.
The University of Pennsylvania Health System (UPHS) includes its flagship hospital, the Hospital of the University of Pennsylvania, rated one of the nation's top ten "Honor Roll" hospitals by U.S.News & World Report; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center. In addition UPHS includes a primary-care provider network; a faculty practice plan; home care, hospice, and nursing home; three multispecialty satellite facilities; as well as the Penn Medicine at Rittenhouse campus, which offers comprehensive inpatient rehabilitation facilities and outpatient services in multiple specialties.
The Abramson Cancer Center (ACC) of the University of Pennsylvania is a national leader in cancer research, patient care, and education. The pre-eminent position of the Cancer Center is reflected in its continuous designation as a Comprehensive Cancer Center by the National Cancer Institute for 30 years, one of 39 such Centers in the United States. The ACC is dedicated to innovative and compassionate cancer care. The clinical program, composed of a dedicated staff of physicians, nurse practitioners, nurses, social workers, physical therapists, nutritionists and patient support specialists, currently sees over 50,000 outpatient visits, 3400 inpatient admissions, and provides over 25,000 chemotherapy treatments, and more than 65,000 radiation treatments annually. Not only is the ACC dedicated to providing state-of-the-art cancer care, the latest forms of cancer prevention, diagnosis, and treatment are available to our patients through clinical themes that developed in the relentless pursuit to eliminate the pain and suffering from cancer. In addition, the ACC is home to the 400 research scientists who work relentlessly to determine the pathogenesis of cancer. Together, the faculty is committed to improving the prevention, diagnosis and treatment of cancer.
Holly Auer | EurekAlert!
Multi-institutional collaboration uncovers how molecular machines assemble
02.12.2016 | Salk Institute
Fertilized egg cells trigger and monitor loss of sperm’s epigenetic memory
02.12.2016 | IMBA - Institut für Molekulare Biotechnologie der Österreichischen Akademie der Wissenschaften GmbH
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.
The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...
Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water
In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...
The efficiency of power electronic systems is not solely dependent on electrical efficiency but also on weight, for example, in mobile systems. When the weight of relevant components and devices in airplanes, for instance, is reduced, fuel savings can be achieved and correspondingly greenhouse gas emissions decreased. New materials and components based on gallium nitride (GaN) can help to reduce weight and increase the efficiency. With these new materials, power electronic switches can be operated at higher switching frequency, resulting in higher power density and lower material costs.
Researchers at the Fraunhofer Institute for Solar Energy Systems ISE together with partners have investigated how these materials can be used to make power...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
02.12.2016 | Medical Engineering
02.12.2016 | Agricultural and Forestry Science
02.12.2016 | Physics and Astronomy