A major international study has identified a novel gene mutation that appears to increase the risk of both inherited and sporadic cases of malignant melanoma, the most deadly form of skin cancer.
The identified mutation occurs in the gene encoding MITF, a transcription factor that induces the production of several important proteins in melanocytes, the cells in which melanoma originates. While previous research has suggested that MITF may act as a melanoma oncogene, the current study identifies a mechanism by which MITF mutation could increase melanoma risk.
The report from researchers from the U.S., the U.K. and Australia is receiving advance online publication in Nature. It is expected to appear in a print issue along with a study from French researchers finding that the same mutation increased the risk for the most common form of kidney cancer, for melanoma or for both tumors.
"We previously knew that MITF is a master regulator for production of the pigment melanin; and several years ago we identified a chemical modification, called sumoylation, that represses MITF activity," says David Fisher, MD, PhD, chief of Dermatology at Massachusetts General Hospital (MGH), director of the MGH Cutaneous Biology Research Center and co-senior author of the Nature paper. "The currently discovered mutation appears to block sumoylation of MITF, and the resulting overactivity of MITF significantly increases melanoma risk."
While around 10 percent of patients with melanoma report a family history of the disease, true hereditary melanoma, involving multiple cases across many generations, probably accounts for 1 percent or less of all cases, says co-senior author Hensin Tsao, MD, PhD, of MGH Dermatology and the Wellman Center for Photomedicine. "Most cutaneous melanomas arise as a result of interaction between environmental factors such as excessive sun exposure and more common, inherited low- to moderate-risk gene variants – such as in the red-hair gene MC1R and this novel variant in MITF."
The investigators began the current study by sequencing the genome of a melanoma patient from a family in which eight cases of melanoma had been reported across three generations – four in first-degree relatives of the patient – but with neither of the two identified high-risk mutations. Among several novel variants they found, the investigators focused on a mutation in MITF, since it had previously been identified as a potential melanoma oncogene. Genetic material was available from six additional affected members of this family, and the same MITF mutation – designated E318K – was found in two of them.
To further analyze the role of this mutation in melanoma risk, the researchers genotyped samples from several large studies conducted in the U.K. and Australia involving more than 15,000 individuals. The E318K mutation occurred more frequently in individuals with melanoma than in healthy controls, and was even more common among families with two or three cases of melanoma. Analysis of the mutation's effects on MITF function confirmed that it reduces sumoylation and increases the transcription of some but not all genes controlled by MITF. The E318K mutation was also associated with increased numbers of the common skin moles called nevi, a recognized risk factor for melanoma, and with a reduced likelihood of blue eye color.
"This MITF variant doubles the background risk for melanoma, which is approximately the same risk increase conferred by severe sunburns; however, an important aspect of this study is the elegant demonstration of how the E318K change affects MITF function " says Tsao. "Furthermore, documenting this moderate level of risk required thousands of cases and controls worldwide, a testament to the unique collaborative nature of this study and the potential utility of next-generation sequencing for gene discovery."
Fisher adds, "We now need to better understand exactly how this mutation causes melanocytes to become cancerous. That information might help us discover other oncogenes as well as find treatment strategies to block the cancer-promoting activity and kill melanoma cells." Fisher is the Wigglesworth Professor of Dermatology, and Tsao is an associate professor of Dermatology at Harvard Medical School.
Co-lead authors of the Nature paper are Satoru Yokoyama from Fisher's laboratory in the MGH Cutaneous Biology Research Center; Susan Woods, Glen Boyle, Lauren Aoude, and Stuart MacGregor, Queensland Institute of Medical Research (QIMR), Australia; and Victoria Zismann, Translational Genomics Research Institute (TGen), Phoenix, Arizona. Additional co-senior authors are Jeffrey Trent, TGen; Nicholas Hayward, QIMR; and Kevin Brown, National Cancer Institute. Support for the study includes major grants from the National Institutes of Health, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, and the Melanoma Research Alliance.
Celebrating the 200th anniversary of its founding in 1811, Massachusetts General Hospital (www.massgeneral.org) is the original and largest teaching hospital of Harvard Medical School. MGH conducts the largest hospital-based research program in the United States, with an annual research budget of nearly $700 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, transplantation biology and photomedicine.
Sue McGreevey | EurekAlert!
Link Discovered between Immune System, Brain Structure and Memory
26.04.2017 | Universität Basel
Researchers develop eco-friendly, 4-in-1 catalyst
25.04.2017 | Brown University
More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.
Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...
Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.
"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...
The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.
Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...
The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...
Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.
Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...
20.04.2017 | Event News
18.04.2017 | Event News
03.04.2017 | Event News
26.04.2017 | Materials Sciences
26.04.2017 | Agricultural and Forestry Science
26.04.2017 | Physics and Astronomy