Tag: melanomas

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Sunlight-fuelled Chemical Changes Drive Melanomas

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Photo by Amy Humphries on Unsplash

Mutations in DNA that lead to melanoma result from a sunlight-fuelled chemical conversion in DNA, not just a DNA copying error as previously believed, according to a new study.

The findings of the study, led by the Van Andel Institute scientists and published in Science Advances, upend long-held beliefs about the mechanisms underlying the disease, reinforce the importance of prevention efforts and offer a path forward for investigating the origins of other cancer types.

“Cancers result from DNA mutations that allow defective cells to survive and invade other tissues,” said corresponding author Gerd Pfeifer, PhD, a VAI professor. “However, in most cases, the source of these mutations is not clear, which complicates development of therapies and prevention methods. In melanoma, we’ve now shown that damage from sunlight primes the DNA by creating ‘premutations’ that then give way to full mutations during DNA replication.”

Melanoma begins in pigment-producing skin cells. Although less common than other types of skin cancer, melanoma is more likely to metastasise, significantly reducing patient survival. Previous studies have shown that melanoma has the most DNA mutations of any cancer. Like other skin cancers, melanoma is linked to sun exposure, specifically UVB radiation which damages cells and DNA.

Most cancers are to arise when damaged DNA causes a mutation that is propagated through subsequent cellular generations. In the case of melanoma, however, Pfeifer and his team found a different mechanism that produces disease-causing mutations – the introduction of a chemical base not normally found in DNA that makes it prone to mutation.

In melanoma, the problem occurs when UVB radiation from the sun hits certain sequences of bases: CC, TT, TC and CT, causing them to chemically link together and become unstable. This resulting instability induces a chemical change to cytosine that transforms it into uracil, a chemical base found in the messenger molecule RNA but not in DNA. This change, called a “premutation,” primes the DNA for mutation during normal cell replication and eventually melanoma.

These mutations may lay dormant for years, not causing disease. More mutations can build up throughout a person’s lifetime exposure to sunlight, resulting in a stubborn cancer that evades many therapeutic options.

“Safe sun practices are very important. In our study, 10–15 minutes of exposure to UVB light was equivalent to what a person would experience at high noon, and was sufficient to cause premutations,” Prof Pfeifer said. “While our cells have built-in safeguards to repair DNA damage, this process occasionally lets something slip by. Protecting the skin is generally the best bet when it comes to melanoma prevention.”

The study used a method developed by Prof Pfeifer’s lab called Circle Damage Sequencing, enabling scientists to ‘break’ DNA at each point where damage occurs. DNA is coaxed into circles and replicated with PCR. With enough DNA, next-generation sequencing then identifies which DNA bases are present at the breaks. Pfeifer and colleagues plan to use this technique going forward to examine other types of DNA damage in different kinds of cancer.

Source: Van Andel Institute (VAI)

Journal reference: Jin, S-G., et al. (2021) The major mechanism of melanoma mutations is based on deamination of cytosine in pyrimidine dimers as determined by circle damage sequencing. Science Advances. doi.org/10.1126/sciadv.abi6508.

Categories : CancerTags :

Study Discovers How Melanoma Cells Hide From Immune System

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Melanomas in some patients do not respond well to immunotherapy treatments, and now researchers have discovered that a defect in STING gene expression in melanoma cells helps them escape immune cell surveillance.

Cancer cells use a variety of recently discovered mechanisms to avoid detection and destruction by immune cells, including defective detection and destruction of T cells, losses in expression of critical proteins on tumour cells and defective cell signaling in both immune and tumor cells.

The interferon signaling pathway is an important signaling pathway in interactions between tumour and immune cells. This pathway increases expression of molecules allowing tumour cells to be targeted by immune cells. One of the interferon signaling pathway’s key molecules is STING, which is activated by the protein cGAS.

Previously Moffitt researchers showed that STING activity is suppressed and altered in a subset of melanomas, rendering tumour cells invisible to the immune system.

Using a process called epigenetic modification to turn genes on or off with methylation groups, the researchers sought to improve the understanding of alterations in STING signaling in melanoma and find out how STING expression is suppressed. 

The researchers performed a series of laboratory experiments and discovered that the DNA regulatory region of the STING gene is highly modified by methylation groups resulting in loss of STING gene expression in certain melanoma cell lines. Importantly, they confirmed these findings in patient clinical samples of early and late-stage melanomas and showed similar methylation events and loss of expression of the upstream STING regulator cGAS.

The researchers demonstrated the possibility of reactivating STING and/or cGAS expression with a demethylating drug or genetic approaches. These successfully reactivated STING activity, resulting in increased interferon levels when triggered by STING agonist drugs that enabled the melanoma cells to now be recognised and targeted by immune cells.

“These studies show the critical importance of an intact STING pathway in melanomas for optimal T cell immunotherapy success, and how to overcome a notable STING defect in melanoma cases of gene hypermethylation by a combination therapy,” said senior author James J. Mulé, PhD, and Associate Center Director, Translational Science, H. Lee Moffitt Cancer Center & Research Institute.”Unless patients’ melanomas are pre-screened for intact versus defective STING, it is not at all surprising that clinical trials of STING agonists have, to date, uniformly failed.”

Source: News-Medical.Net

Journal information: Falahat, R., et al. (2021) Epigenetic reprogramming of tumor cell–intrinsic STING function sculpts antigenicity and T cell recognition of melanoma. Proceedings of the National Academy of Sciences. doi.org/10.1073/pnas.2013598118.

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Neural Network Matches Dermatologists’ Assessment of Skin Lesions

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Researchers have developed an AI-based tool that can use smartphone camera pictures to spot suspicious pigmented lesions (SPLs) with an accuracy close to that of professional dermatologists.

Such technology would hardly put dermatologists out of work; on the contrary, there is a great need for readily available skin cancer screening. In the US, there are only 12 000 practising dermatologists, who would need to see over 27 000 patients each per year in order to screen the entire population for SPLs which could lead to cancer. Computer-aided diagnosis (CAD) has thus been developed over previous years to help assist in diagnosis, but thus far had failed to spot melanomas in a meaningful way. Such CAD programs only analyse individual SPLs, while dermatologists compare other lesions on the same patient to reach a diagnosis, called ‘ugly duckling’ criteria.

This shortcoming has been addressed in a new CAD system that uses convolutional deep neural networks (CDNNs) developed by researchers at the Wyss Institute for Biologically Inspired Engineering at Harvard University and the Massachusetts Institute of Technology (MIT).

The new system was able to distinguish SPLs from non-suspicious lesions in photos of patients’ skin at ~90% accuracy, and established an ‘ugly duckling’ criteria which could match three dermatologists’ consensus 88% of the time.

“We essentially provide a well-defined mathematical proxy for the deep intuition a dermatologist relies on when determining whether a skin lesion is suspicious enough to warrant closer examination,” said first author Luis Soenksen, PhD, a Postdoctoral Fellow at the Wyss Institute who is also a Venture Builder at MIT. “This innovation allows photos of patients’ skin to be quickly analyzed to identify lesions that should be evaluated by a dermatologist, allowing effective screening for melanoma at the population level.”

The researchers used a database of 33 000 images to train the system, which also included background elements and non-skin elements. These extraneous elements were left in so that the CDNN would be able to use normal images taken by consumer-grade cameras. The images contained SPLs and non-suspicious skin lesions identified by three certified dermatologists.
The software then developed a ‘map’ of how far away a lesion was from the others in terms of similarity, giving an ‘ugly duckling’ criteria. To test the software, they used 135 photos from 68 patients, which assigned an ‘oddness’ score to each lesion. This was then compared to dermatologists’ assessments of those lesions, matching individual dermatologists 88% of the time and their consensus 86% of the time
“This high level of consensus between artificial intelligence and human clinicians is an important advance in this field, because dermatologists’ agreement with each other is typically very high, around 90%,” said co-author Jim Collins, PhD, of the Wyss Institute, who is also the Termeer Professor of Medical Engineering and Science at MIT. “Essentially, we’ve been able to achieve dermatologist-level accuracy in diagnosing potential skin cancer lesions from images that can be taken by anybody with a smartphone, which opens up huge potential for finding and treating melanoma earlier.”

Source: Medical Xpress

Journal information: “Using deep learning for dermatologist-level detection of suspicious pigmented skin lesions from wide-field images” Science Translational Medicine, 2021.