Scientists identify another frequently mutated gene in melanoma

28 Jul

The part played by genetic mutations in the development of melanoma is well established and

many genes and genomic changes involved have been identified. However, in around 30% of melanomas,

the genetic culprits are less clear. Now, a new study has defined a subgroup of mutations that are

present in a significant number of melanomas and identifies a new major player.

For the study, the researchers analyzed mutations in over

200 melanoma samples from patients with the disease.

In describing their findings in the journal Nature Genetics, researchers from Yale

University in New Haven, CT, hope they will lead to more targeted therapies for this most

aggressive skin cancer.

Although melanoma is the least common skin cancer, it is responsible for the most deaths. The American Cancer Society estimate that in 2015, around 73,800

Americans will discover they have melanoma and around 9,900 will die from it.

Melanoma starts in pigment-producing cells called melanocytes. While it is not clear exactly how

it happens, it is thought that certain clusters of genetic mutations reduce a person’s ability to

resist the damage that ultraviolet (UV) radiation – such as that from the sun’s rays – inflicts on the

DNA in the cells. This damage affects certain genes that control how skin cells grow and divide,

giving rise to tumors.

For their study, the Yale researchers used whole exome sequencing to analyze mutations in over

200 melanoma samples from patients with the disease.

The team – which included experts in genetics, pharmacology, cancer and computational biology –

also ran experiments to see how tumor cells with particular mutations responded to anticancer


NF1 is a ‘major player’ in development of melanoma

The researchers confirmed that a gene called NF1 is a “major player” in the development of

melanoma. In their paper, they note their analysis establishes NF1 as the “third most frequently

mutated gene in melanoma, after BRAF and NRAS.”

Lead and corresponding author Michael Krauthammer, an associate professor of pathology, also


“The key finding is that roughly 45% of melanomas that do not harbor the known BRAF or

NRAS mutations display loss of NF1 function, which leads to activation of the same cancer-causing


The analysis also reveals that the NF1 mutation mostly arose in samples from older patients with

more mutations in their tumors. These include mutations in genes that affect the same signaling

pathway, known collectively as RASopathy genes.

However, note the authors, while NF1 is the third most commonly mutated gene, on its own it does

not cause cancer. A cluster of genetic changes, of which mutated NF1 is but one, is required to

make a tumor.

Lead author Dr. Ruth Halaban, a senior research scientist in dermatology, concludes:

“Our study identified changes in about 100 genes that are present only in the

malignant cells and are likely to be causative. This panel of genes can now be used in precision medicine to diagnose malignant lesions and can

be applied to personalized cancer treatment.”

The researchers also found that several factors, in addition to loss of NF1, can affect response

to anticancer drugs, which Dr. Halaban says “opens the door to more research.”

Funds from the National Institutes of Health, the Melanoma Research Alliance, Gilead Sciences

and the Howard Hughes Medical Institute helped finance the study.

Earlier this year, Medical News Today learned of a study that found a quarter of healthy skin cells possess cancer-related mutations.

In the journal Science, researchers from the Wellcome Trust Sanger Institute explain

how after examining skin samples from healthy people, they uncovered more than 100 cancer-associated mutations in every square centimeter of skin.

Written by Catharine Paddock PhD

Copyright: Medical News Today

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