Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Scientists discover melanoma-driving genetic changes caused by sun damage

20.07.2012
New approach sorts cancer 'driver' mutations from abundant but irrelevant 'passengers'

It's been a burning question in melanoma research: Tumor cells are full of ultraviolet (UV)-induced genetic damage caused by sunlight exposure, but which mutations drive this cancer?

None have been conclusively tied to melanoma. The sheer abundance of these passenger mutations has obscured the search for genetic driver mutations that actually matter in melanoma development and progression.

By creating a method to spot the drivers in a sea of passengers, scientists at the Broad Institute of MIT and Harvard, the Dana-Farber Cancer Institute and The University of Texas MD Anderson Cancer Center have identified six genes with driving mutations in melanoma, three of which have recurrent 'hotspot' mutations as a result of damage inflicted by UV light. Their findings are reported in the July 20 issue of the journal Cell.

"Those three mutations are the first 'smoking gun' genomic evidence directly linking damage from UV light to melanoma," said co-senior author Lynda Chin, M.D., Professor and Chair of MD Anderson's Department of Genomic Medicine. "Until now, that link has been based on epidemiological evidence and experimental data."

"This study also is exciting because many of the recent large-scale genomic studies have not discovered new cancer genes with recurrent hot-spot mutations, a pattern strongly indicative of biological importance," said Chin, who also is scientific director of MD Anderson's Institute for Applied Cancer Science.

The six new melanoma genes identified by the team are all significantly mutated and provide potential targets for new treatments.

Puzzle has thousands of potential pieces, but only requires a few dozen

A number of important mutations had previously been identified as melanoma drivers. These include BRAF (V600) mutations, present in half of all melanomas, and NRAS (Q61) mutations. However, the vast majority of these mutations do not appear to be caused by direct damage from UV light exposure.

Those known mutations are important, but don't tell the whole story. Melanoma, the authors note, has higher genetic mutation rates than most other types of solid tumors. The majority are attributable to passenger mutations caused by UV light damage resulting in a DNA alteration called a cytidine (C) to thymidine (T) transition.

Chin together with Levi A. Garraway M.D, Ph.D., associate professor at Dana-Farber Cancer Institute and Harvard Medical School and senior associate member at the Broad Institute, sequenced the exons – active portions of DNA involved in protein synthesis – in 121 melanoma samples paired with normal DNA and found 86,813 coding mutations. The resulting mutation rate was higher than that ever reported in any other tumor type.

Among the most frequently mutated genes, 85 percent of the active coding mutations resulted from C to T transitions caused by UV light exposure.

Statistical approaches to identify driver mutations have often assumed that the baseline mutation rate is uniform across the genome. The abundance of UV-induced passenger mutations that vary in frequency confounds this assumption in melanoma, the researchers report.

"When a gene is found to be repeatedly mutated, we naturally assume that it must be important to the cancer," said Garraway, who is co-senior author with Chin on the study. "However, melanoma can fool us – in that cancer, the very high mutation rate means that many genes can be recurrently mutated purely by chance. We needed a solution to this problem."

To counter this effect, the researchers turned to parts of the genome that don't code for proteins, called introns, and other inactive DNA segments that flank exons. By comparing the frequency of mutations in the inactive segments to the frequency of mutations in the exons, the researchers built a framework for assessing the statistical significance of functional mutations.

Approach identifies six known cancer genes, six new ones

The analysis identified functional mutations in the well-known cancer genes BRAF, NRAS, PTEN, TP53, CDKN2A and MAP2K1.

It also uncovered five new genes, RAC1, PPP6C, STK19, SNX31, and TACC1. Most are associated with molecular pathways involved in cancer but had not been previously recognized as significantly mutated in melanoma. Their presence in the tumor samples ranged from 3 percent to 9 percent.

The sixth new gene tied to melanoma was ARID2, an apparent tumor-suppressor gene possessing a significant number of loss-of-function mutations found in 7% of patient samples.

"Six new melanoma genes have been picked out from thousands of mutated genes," said Eran Hodis, co-lead author who is a computational biologist in the Garraway lab at the Broad Institute and an M.D.-Ph.D. student at Harvard and MIT. "The same approach may bring clarity to genome sequencing studies of other cancers plagued by high passenger mutation rates, for example lung cancer."

UV damage causes 46 percent of driver mutations

The team then cross-referenced their findings with a database of recurrent mutations called COSMIC and gained new insights in the frequency and characteristics of driver mutations, old and newly discovered, in 21 genes.

Out of 262 driver mutations in the 21 genes, 46 percent were caused by UV-induced damage. The well-known tumor-suppressing gene TP53 had the greatest number of UV-caused mutations. Other tumor-suppressors also had loss-of-function mutations and all of the newly identified genes had a high percentage of mutations caused by UV damage.

Most exciting, three of the discovered genes possessed 'hotspot' mutations found in the exact same position in multiple patients providing another line of evidence indicating these mutations contribute to melanoma.

"We have now discovered the third most common hotspot mutation found in melanoma is present in a gene called RAC1, and unlike BRAF and NRAS mutations, this activating mutation is attributable solely to characteristic damage inflicted by sunlight exposure" said Ian R. Watson, Ph.D., co-lead author of the study and postdoctoral fellow in the Chin lab at MD Anderson.

New insights provide opportunity to better understand, treat melanoma

Much work remains following the most comprehensive analysis of the genetics of melanoma, the authors noted. If diagnosed early, melanoma is highly curable, but in its metastatic stage is lethal. Determining the role these mutated genes play in biological processes important for melanoma progression and metastasis provides a new avenue of investigation into the molecular basis of this disease.

With the advent of the BRAF inhibitor vemurafenib, melanoma has emerged as the latest success story for genomics-guided targeted therapy in treatment of patients with metastatic disease. However, melanoma eventually resists this therapy and effective treatment options for patients that do not possess a BRAF (V600) mutation are limited.

Determining whether these newly discovered genes are amenable to targeted therapy, or whether their mutations predict sensitivity to currently available drugs, Chin said, will be an important next step in translating these findings into the clinic.

This work was supported by grants from the National Institutes of Health, including the National Human Genome Research Institute Large Scale Sequencing Program, Grant U54 HG003067, to the Broad Institute; the Melanoma Research Alliance; the University of Texas MD Anderson Cancer Center Melanoma Specialized Program of Research Excellence and Melanoma Informatics, Tissue Resource, and Pathology (Core grant P50 CA93459); MD Anderson's NCI Cancer Center Support Grant (CA-16672); the Canadian Institutes of Health; the Swiss National Science Foundation (PASMP3_134379/1); the G. Harold and Leila Y. Mathers Charitable Foundation; the FWF-Austrian Science Fund (L590-B12); an NIH New Innovator Award (DP2OD002750), NCI (R33CA126674), the Starr Cancer Consortium, National Cancer Institute grant (R01 CA093947), The Cancer Genome Atlas of the NIH (U24 CA143845) the Milestein Innovation Award in Melanoma Research and the Cancer Prevention and Research Institute of Texas.

Laura Sussman | EurekAlert!
Further information:
http://www.mdanderson.org

More articles from Life Sciences:

nachricht The secret sulfate code that lets the bad Tau in
16.07.2018 | American Society for Biochemistry and Molecular Biology

nachricht Colorectal cancer risk factors decrypted
13.07.2018 | Max-Planck-Institut für Stoffwechselforschung

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: First evidence on the source of extragalactic particles

For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.

To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...

Im Focus: Magnetic vortices: Two independent magnetic skyrmion phases discovered in a single material

For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.

Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...

Im Focus: Breaking the bond: To take part or not?

Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.

A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...

Im Focus: New 2D Spectroscopy Methods

Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.

"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....

Im Focus: Chemical reactions in the light of ultrashort X-ray pulses from free-electron lasers

Ultra-short, high-intensity X-ray flashes open the door to the foundations of chemical reactions. Free-electron lasers generate these kinds of pulses, but there is a catch: the pulses vary in duration and energy. An international research team has now presented a solution: Using a ring of 16 detectors and a circularly polarized laser beam, they can determine both factors with attosecond accuracy.

Free-electron lasers (FELs) generate extremely short and intense X-ray flashes. Researchers can use these flashes to resolve structures with diameters on the...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Leading experts in Diabetes, Metabolism and Biomedical Engineering discuss Precision Medicine

13.07.2018 | Event News

Conference on Laser Polishing – LaP: Fine Tuning for Surfaces

12.07.2018 | Event News

11th European Wood-based Panel Symposium 2018: Meeting point for the wood-based materials industry

03.07.2018 | Event News

 
Latest News

Leading experts in Diabetes, Metabolism and Biomedical Engineering discuss Precision Medicine

13.07.2018 | Event News

Research finds new molecular structures in boron-based nanoclusters

13.07.2018 | Materials Sciences

Algae Have Land Genes

13.07.2018 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>