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 Designer cells: artificial enzyme can activate a gene switch
22.05.2018 | Universität Basel

nachricht Flow of cerebrospinal fluid regulates neural stem cell division
22.05.2018 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: LZH showcases laser material processing of tomorrow at the LASYS 2018

At the LASYS 2018, from June 5th to 7th, the Laser Zentrum Hannover e.V. (LZH) will be showcasing processes for the laser material processing of tomorrow in hall 4 at stand 4E75. With blown bomb shells the LZH will present first results of a research project on civil security.

At this year's LASYS, the LZH will exhibit light-based processes such as cutting, welding, ablation and structuring as well as additive manufacturing for...

Im Focus: Self-illuminating pixels for a new display generation

There are videos on the internet that can make one marvel at technology. For example, a smartphone is casually bent around the arm or a thin-film display is rolled in all directions and with almost every diameter. From the user's point of view, this looks fantastic. From a professional point of view, however, the question arises: Is that already possible?

At Display Week 2018, scientists from the Fraunhofer Institute for Applied Polymer Research IAP will be demonstrating today’s technological possibilities and...

Im Focus: Explanation for puzzling quantum oscillations has been found

So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics

Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...

Im Focus: Dozens of binaries from Milky Way's globular clusters could be detectable by LISA

Next-generation gravitational wave detector in space will complement LIGO on Earth

The historic first detection of gravitational waves from colliding black holes far outside our galaxy opened a new window to understanding the universe. A...

Im Focus: Entangled atoms shine in unison

A team led by Austrian experimental physicist Rainer Blatt has succeeded in characterizing the quantum entanglement of two spatially separated atoms by observing their light emission. This fundamental demonstration could lead to the development of highly sensitive optical gradiometers for the precise measurement of the gravitational field or the earth's magnetic field.

The age of quantum technology has long been heralded. Decades of research into the quantum world have led to the development of methods that make it possible...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Save the date: Forum European Neuroscience – 07-11 July 2018 in Berlin, Germany

02.05.2018 | Event News

Invitation to the upcoming "Current Topics in Bioinformatics: Big Data in Genomics and Medicine"

13.04.2018 | Event News

Unique scope of UV LED technologies and applications presented in Berlin: ICULTA-2018

12.04.2018 | Event News

 
Latest News

Designer cells: artificial enzyme can activate a gene switch

22.05.2018 | Life Sciences

PR of MCC: Carbon removal from atmosphere unavoidable for 1.5 degree target

22.05.2018 | Earth Sciences

Achema 2018: New camera system monitors distillation and helps save energy

22.05.2018 | Trade Fair News

VideoLinks
Science & Research
Overview of more VideoLinks >>>