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!
Rainbow colors reveal cell history: Uncovering β-cell heterogeneity
22.09.2017 | DFG-Forschungszentrum für Regenerative Therapien TU Dresden
The pyrenoid is a carbon-fixing liquid droplet
22.09.2017 | Max-Planck-Institut für Biochemie
Plants and algae use the enzyme Rubisco to fix carbon dioxide, removing it from the atmosphere and converting it into biomass. Algae have figured out a way to increase the efficiency of carbon fixation. They gather most of their Rubisco into a ball-shaped microcompartment called the pyrenoid, which they flood with a high local concentration of carbon dioxide. A team of scientists at Princeton University, the Carnegie Institution for Science, Stanford University and the Max Plank Institute of Biochemistry have unravelled the mysteries of how the pyrenoid is assembled. These insights can help to engineer crops that remove more carbon dioxide from the atmosphere while producing more food.
A warming planet
Our brains house extremely complex neuronal circuits, whose detailed structures are still largely unknown. This is especially true for the so-called cerebral cortex of mammals, where among other things vision, thoughts or spatial orientation are being computed. Here the rules by which nerve cells are connected to each other are only partly understood. A team of scientists around Moritz Helmstaedter at the Frankfiurt Max Planck Institute for Brain Research and Helene Schmidt (Humboldt University in Berlin) have now discovered a surprisingly precise nerve cell connectivity pattern in the part of the cerebral cortex that is responsible for orienting the individual animal or human in space.
The researchers report online in Nature (Schmidt et al., 2017. Axonal synapse sorting in medial entorhinal cortex, DOI: 10.1038/nature24005) that synapses in...
Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...
Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!
When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...
For the first time, physicists have successfully imaged spiral magnetic ordering in a multiferroic material. These materials are considered highly promising candidates for future data storage media. The researchers were able to prove their findings using unique quantum sensors that were developed at Basel University and that can analyze electromagnetic fields on the nanometer scale. The results – obtained by scientists from the University of Basel’s Department of Physics, the Swiss Nanoscience Institute, the University of Montpellier and several laboratories from University Paris-Saclay – were recently published in the journal Nature.
Multiferroics are materials that simultaneously react to electric and magnetic fields. These two properties are rarely found together, and their combined...
19.09.2017 | Event News
12.09.2017 | Event News
06.09.2017 | Event News
22.09.2017 | Life Sciences
22.09.2017 | Medical Engineering
22.09.2017 | Physics and Astronomy