Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Newly identified gene mutation adds to melanoma risk

14.11.2011
Findings suggest how oncogene increases risk of deadly tumor, may lead to better treatment

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!
Further information:
http://www.massgeneral.org

More articles from Life Sciences:

nachricht Repairing damaged hearts with self-healing heart cells
22.08.2017 | National University Health System

nachricht Biochemical 'fingerprints' reveal diabetes progression
22.08.2017 | Umea University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Fizzy soda water could be key to clean manufacture of flat wonder material: Graphene

Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.

As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...

Im Focus: Exotic quantum states made from light: Physicists create optical “wells” for a super-photon

Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.

Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...

Im Focus: Circular RNA linked to brain function

For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.

While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...

Im Focus: RAVAN CubeSat measures Earth's outgoing energy

An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.

The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...

Im Focus: Scientists shine new light on the “other high temperature superconductor”

A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.

Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Call for Papers – ICNFT 2018, 5th International Conference on New Forming Technology

16.08.2017 | Event News

Sustainability is the business model of tomorrow

04.08.2017 | Event News

Clash of Realities 2017: Registration now open. International Conference at TH Köln

26.07.2017 | Event News

 
Latest News

Cholesterol-lowering drugs may fight infectious disease

22.08.2017 | Health and Medicine

Meter-sized single-crystal graphene growth becomes possible

22.08.2017 | Materials Sciences

Repairing damaged hearts with self-healing heart cells

22.08.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>